Novel compound and pharmaceutical composition containing the same

ABSTRACT

Disclosed are compounds of formula (I) below and pharmaceutically acceptable salts thereof: Formula (I), in which each of variables L, R 3 , R 4 , Y, Z 1 , Z 2  and Z 3  is defined herein. Also disclosed is a method for treating a cancer with a compound of formula (I) or a salt thereof and a pharmaceutical composition containing same.

This application claims the benefit of filing date of U.S. ProvisionalApplication Ser. No. 62/540,114, filed Aug. 2, 2017, which is herebyincorporated by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to compounds that can inhibit the growthof tumer cells, pharmaceutical compositions comprising the compounds,and the uses of the compounds or compositions.

BACKGROUND

Foods or food additives, and environmental pollutions have been a sourceof contention as a cause or catalyst for promoting cancer in recentyears. Not coincidentally, the same event is happening as well in thedeveloped countries and around the world, positing as an alarming signthat the incidence rates of cancers are quite high. According to thedata published by the American Cancer Society, cancer is being proved tobe the most significant threat to public health.

The general methods for treating cancer include surgery, radiotherapy,chemotherapy and immune therapy. In recent years, the development ofseveral therapeutic agents has lead to cancer treatments through newanti-cancer mechanisms, and it has been proven that the survival rate ofpatients can be increased by treating them with these therapeuticagents. Generally, the therapeutic agents can treat cancers throughinhibition of cell cycle progression, angiogenesis, farnesyltransferase, and tyrosine kinases.

Although it is known that certain agents exhibit therapeutic effects oncancer, these agents do have their limitations. For example, “Gefitinib”is a drug for inhibiting non-small cell lung cancer, but it fails tocure in most cases. Also, it has no effects on blocking the progressionof breast and colorectal cancers. In addition, the therapeutic effectsof the anti-cancer drugs also depend on the locations of tumor cells,genetic variations of patients, and the side effects of drugs.Furthermore, cancer cells may become malignant and spread from itsoriginal sites to target organs via the lymphatic system or bloodstream,thereby establishing metastatic cancers.

Since the risk of developing cancer generally increases with age, theoccurrence rates of cancer go up as more people live to an old age andas mass lifestyle changes. Hence, there is a long unfulfilled need toprovide new agents for cancer treatment and prevention.

SUMMARY

The present disclosure relates to certain compounds that can inhibit thegrowth of tumor cells.

An aspect of this disclosure is drawn to the compounds of formula (I)below and pharmaceutically acceptable salts thereof:

In this formula, Z₁ is N or C—R₂; Z₂ is C or N; and Z₃ is N or C—X—R₁,with the proviso that no more than two of Z₁, Z₂ and Z₃ are N. X is adirect bond, —(CH₂)_(n)—, —O—, —(C═O)NH— or —(C═O)—, in which n is 1, 2or 3, and R_(a) is hydrogen or alkyl. Y is —CH—, O or S, in which R_(b)is hydrogen or alkyl. L is a direct bond, —(CH₂)_(m)— or —NH—, in whichm is 1, 2 or 3. R₁ is hydrogen, halogen, cyano, alkyl, alkyloxy,cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each ofalkyloxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl isoptionally substituted with one to three moieties selected from thegroup consisting of halogen, hydroxyl, nitro, cyano, —NR_(c)R_(d), loweralkyl carbamoyl, heterocycloalkyl, alkyl optionally substituted with oneto three halo or aryl, and alkyloxy optionally substituted with one tothree halo, alkyloxy, cycloalkyl, heterocycloalkyl, —NR_(e)R_(f) oraryl, in which each of R_(e), R_(d), R_(e) and R_(f) independently ishydrogen or alkyl. R₂ is hydrogen, halogen, alkyl, alkyloxy, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein each of alkyloxy,cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionallysubstituted with one to three moieties selected from the groupconsisting of halogen, hydroxyl, nitro, cyano, —NR_(g)R_(h), lower alkylcarbamoyl, alkynyl, alkyl optionally substituted with one to three halo,and alkyloxy optionally substituted with one to three halo or alkyloxy,in which each of R_(g) and R_(h) independently is hydrogen or alkyl. R₃is

in which M is O or S. And, R₄ is H or alkyl.

The term “alkyl” herein refers to a straight or branched hydrocarbongroup, containing 1-12 carbon atoms (e.g., C₁-C₁₀, C₁-C₈ and C₁-C₆).Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,and t-butyl.

The term “alkynyl” herein refers to a straight or branched monovalent orbivalent hydrocarbon containing 2-20 carbon atoms (e.g., C₂-C₁₆, C₂-C₁₂,C₂-C₈, C₂-C₆ and C₂-C₄) and one or more triple bonds. Examples ofalkynyl include, but are not limited to, ethynyl, ethynylene,1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl.

The term “cycloalkyl” refers to a saturated and partially unsaturatedmonocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group having3-12 (e.g., 3-10 and 3-7) carbon atoms. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cyclooctyl.

The term “heterocycloalkyl” refers to a nonaromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having one or more heteroatoms (e.g., 0, N, P, and S). Examplesinclude piperazinyl, imidazolidinyl, azepanyl, pyrrolidinyl,dihydrothiadiazolyl, dioxanyl, morpholinyl, tetrahydropuranyl, andtetrahydrofuranyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Examplesinclude methoxy, ethoxy, propoxy, and isopropoxy.

The term “halogen” refers to a fluoro, chloro, bromo, or iodo radical.

The term “amino” refers to a radical derived from amine, which isunsubstituted or mono-/di-substituted with alkyl, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic,14-carbon tricyclic aromatic ring system. Examples of aryl groupsinclude phenyl, naphthyl, and anthracenyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system havingone or more heteroatoms (e.g., O, N, P, and S). Examples includethiophenyl, triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl,pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl,quinolinyl, indolyl, thiazolyl, and benzothiazolyl.

The term “lower alkyl carbamoyl” refers to a —N(alkyl)₂-C(═O)—O-group,wherein the alkyl refers to a straight or branched hydrocarbon groupcontaining 1-4 carbon atoms, such as methyl or ethyl.

Alkyl, cycloalkyl, heterocycloalkyl, alkyloxy, aryl, and heteroarylmentioned herein include both substituted and unsubstituted moieties.Possible substituents on cycloalkyl, heterocycloalkyl, alkoxy, aryl, andheteroaryl include, but are not limited to, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, C₁₋₁₂heterocycloalkyl, C₁₋₁₂ heterocycloalkenyl, C₁₋₆ alkoxy, aryl, aryloxy,heteroaryl, heteroaryloxy, amino, C₁₋₆ alkylamino, C₁₋₂₀ dialkylamino,arylamino, diarylamino, C₁₋₆ alkylsulfonamino, arylsulfonamino, C₁₋₆alkylimino, arylimino, C₁₋₆ alkylsulfonimino, arylsulfonimino, hydroxyl,halo, thio, C₁₋₆ alkylthio, arylthio, C₁₋₆ alkylsulfonyl, arylsulfonyl,acylamino, aminoacyl, aminothioacyl, amido, amidino, guanidine, ureido,thioureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy,carboxyl, and carboxylic ester. On the other hand, possible substituentson alkyl include all of the above-recited substituents except C₁₋₆alkyl. Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can also befused with each other.

In addition to the compounds of formula (I) described above, theirpharmaceutically acceptable salts and solvates, where applicable, arealso covered by this disclosure. A salt can be formed between an anionand a positively charged group (e.g., amino) on a compound. Examples ofa suitable anion include chloride, bromide, iodide, sulfate, nitrate,phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate,tosylate, tartrate, fumurate, glutamate, glucuronate, lactate,glutarate, and maleate. A salt can also be formed between a cation and anegatively charged group. Examples of a suitable cation include sodiumion, potassium ion, magnesium ion, calcium ion, and an ammonium cationsuch as tetramethylammonium ion. A salt further includes thosecontaining quaternary nitrogen atoms. A solvate refers to a complexformed between an active compound and a pharmaceutically acceptablesolvent. Examples of a pharmaceutically acceptable solvent includewater, ethanol, isopropanol, ethyl acetate, acetic acid, andethanolamine.

Another aspect of this disclosure is a pharmaceutical composition fortreating a cancer.

The pharmaceutical composition contains one of the compounds of formula(I) described above or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier, excipient or diluent.

This disclosure also covers use of such a composition for themanufacture of a medicament for treating treating a cancer.

A composition for oral administration can be any orally acceptabledosage form including capsules, tablets, emulsions and aqueoussuspensions, dispersions, and solutions. In the case of tablets,commonly used carriers include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions or emulsions areadministered orally, the active ingredient can be suspended or dissolvedin an oily phase combined with emulsifying or suspending agents. Ifdesired, certain sweetening, flavoring, or coloring agents can be added.Oral solid dosage forms can be prepared by spray dried techniques; hotmelt extrusion strategy, micronization, and nano milling technologies.

A nasal aerosol or inhalation composition can be prepared according totechniques well known in the art of pharmaceutical formulation. Forexample, such a composition can be prepared as a solution in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters, fluorocarbons, and/or other solubilizing or dispersing agentsknown in the art. A composition having an active compound can also beadministered in the form of suppositories for rectal administration.

The carrier, the excipient and the diluent in the pharmaceuticalcomposition must be “acceptable” in the sense that it is compatible withthe active ingredient of the composition (and preferably, capable ofstabilizing the active ingredient) and not deleterious to the subject tobe treated. One or more solubilizing agents can be utilized aspharmaceutical excipients for delivery of an active compound. Examplesof other carriers include colloidal silicon oxide, magnesium stearate,cellulose, sodium lauryl sulfate, and D&C Yellow #10.

Still within the scope of the present disclosure is a method of treatingtreating a cancer.

The method includes administering to a subject in need thereof aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

The above-described compounds or a pharmaceutical composition containingone or more of them can be administered to a subject orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, or via an implanted reservoir. The term “parenteral” as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional, and intracranial injection orinfusion techniques.

The term “treating”, “treat” or “treatment” refers to application oradministration of the compound to a subject with the purpose to cure,alleviate, relieve, alter, remedy, improve, or affect the disease, thesymptom, or the predisposition. “An effective amount” refers to theamount of the compound which is required to confer the desired effect onthe subject. Effective amounts vary, as recognized by those skilled inthe art, depending on route of administration, excipient usage, and thepossibility of co-usage with other therapeutic treatments such as use ofother active agents.

The details of one or more embodiments of the disclosure are set forthin the description below. Other features, objects, and advantages of thedisclosure will be apparent from the description and from the claims.

DETAILED DESCRIPTION

A first embodiment of the present disclosure is the compounds of formula(I) or pharmaceutically acceptable salts thereof:

in which each of variables each of variables L, R₃, R₄, Y, Z₁, Z₂ and Z₃is defined as in the SUMMARY section.

A second embodiment of the present disclosure is the compound of thefirst embodiment or a pharmaceutically acceptable salt thereof,

A third embodiment of the present disclosure is the compound of thefirst or second embodiments or a pharmaceutically acceptable saltthereof, wherein

A fourth embodiment of the present disclosure is the compound of any oneof the first to third embodiments or a pharmaceutically acceptable saltthereof, wherein X is a direct bond.

A fifth embodiment of the present disclosure is the compound of any oneof the first to fourth embodiments or a pharmaceutically acceptable saltthereof, wherein L is a —CH₂—, and R₃ is

A sixth embodiment of the present disclosure is the compound of any oneof the first to fifth embodiments or a pharmaceutically acceptable saltthereof, wherein R₁ is aryl or heteroaryl, wherein each of aryl andheteroaryl is optionally substituted with one to three moieties selectedfrom the group consisting of halogen, hydroxyl, nitro, cyano,—NR_(c)R_(d), lower alkyl carbamoyl, heterocycloalkyl, alkyl optionallysubstituted with one to three halo or aryl, and alkyloxy optionallysubstituted with one to three halo, alkyloxy, cycloalkyl,heterocycloalkyl, —NR_(e)R_(f) or aryl, in which each of R_(e), R_(d),R_(e) and R_(f) independently is hydrogen, methyl or ethyl.

A seventh embodiment of the present disclosure is the compound of anyone of the first to sixth embodiments or a pharmaceutically acceptablesalt thereof, wherein R₁ is phenyl or pyridinyl, wherein each of phenylor pyridinyl is optionally substituted with one to three alkyloxyoptionally substituted with one to three halo, alkyloxy, cycloalkyl,heterocycloalkyl, —NR_(e)R_(f) or aryl, in which each of R_(c), R_(d),R_(e) and R_(f) independently is hydrogen, methyl or ethyl.

An eighth embodiment of the present disclosure is the compound of anyone of the first to seventh embodiments or a pharmaceutically acceptablesalt thereof, wherein R₄ is H or methyl.

A ninth embodiment of the present disclosure is the compound of any oneof the first to eighth embodiments or a pharmaceutically acceptable saltthereof, wherein L is a —CH₂—; R₃ is

R₄ is H or methyl; and R₁ is phenyl or pyridinyl, wherein each of phenylor pyridinyl is optionally substituted with one or two ethoxy, butoxy,methoxy substituted with ethoxy, or ethoxy substituted withdimethylamino.

A tenth embodiment of the present disclosure is the compound of thefirst or second embodiments or a pharmaceutically acceptable saltthereof, wherein

A eleventh embodiment of the present disclosure is the compound of anyone of the first, second and tenth embodiments or a pharmaceuticallyacceptable salt thereof, wherein X is a direct bond, —CH₂—, —O—,—N(CH₃)—, —(C═O)NH— or —(C═O)—.

An twelfth embodiment of the present disclosure is the compound of anyone of the first, second, tenth and eleventh embodiments or apharmaceutically acceptable salt thereof, wherein L is a direct bond,and R₃ is

in which M is O or S.

A thirteenth embodiment of the present disclosure is the compound of anyone of the first, second, tenth to twelfth embodiments or apharmaceutically acceptable salt thereof, wherein L is a —CH₂—, and R₃is

A fourteenth embodiment of the present disclosure is the compound of anyone of the first, second, tenth to thirteenth embodiments or apharmaceutically acceptable salt thereof, wherein R₁ is hydrogen,halogen, cyano, alkoxy, aryl or heteroaryl, wherein each of aryl andheteroaryl is optionally substituted with one to three moieties selectedfrom the group consisting of halogen, hydroxyl, nitro, cyano,—NR_(c)R_(d), lower alkyl carbamoyl, heterocycloalkyl, alkyl optionallysubstituted with one to three halo or aryl, and alkyloxy optionallysubstituted with one to three halo, alkyloxy, cycloalkyl,heterocycloalkyl, —NR_(e)R_(f) or aryl, in which each of R_(c), R_(d),R_(e) and R_(f) independently is hydrogen, methyl or ethyl.

A fifteenth embodiment of the present disclosure is the compound of anyone of the first, second, tenth to fourteenth embodiments or apharmaceutically acceptable salt thereof, wherein R₁ is phenyl, which isoptionally substituted with one to three moieties selected from thegroup consisting of halogen and alkyl optionally substituted with one tothree halo.

A sixteenth embodiment of the present disclosure is the compound of anyone of the first, second, tenth to fifteenth embodiments or apharmaceutically acceptable salt thereof, wherein R₂ is aryl orheteroaryl, wherein each of aryl and heteroaryl is optionallysubstituted with one to three moieties selected from the groupconsisting of halogen, nitro, cyano, lower alkyl carbamoyl, alkynyl,alkyl optionally substituted with one to three halo, and alkyloxyoptionally substituted with one to three halo or alkyloxy.

A seventeenth embodiment of the present disclosure is the compound ofany one of the first, second, tenth to sixteenth embodiments or apharmaceutically acceptable salt thereof, wherein R₂ is phenyl, which isoptionally substituted with one to three moieties selected from thegroup consisting of halogen, alkyl optionally substituted with one tothree halo, and alkyloxy.

An eighteenth embodiment of the present disclosure is the compound ofany one of the first, second, tenth to seventeenth embodiments or apharmaceutically acceptable salt thereof, wherein R₄ is H or methyl.

A nineteenth embodiment of the present disclosure is the compound of anyone of the first, second, tenth to eighteenth embodiments or apharmaceutically acceptable salt thereof, wherein X is —O—; L is adirect bond; R₃ is

in which M is S; R₄ is H; R₁ is phenyl optionally substituted withfluoro, tert-pentyl or trifluoromethyl; and R₂ is phenyl substitutedwith ethoxy, butoxy, fluoro, tert-butyl, tert-pentyl or trifluoromethyl.

A twentieth embodiment of the present disclosure is the compound of anyone of the first, second, tenth to eighteenth embodiments or apharmaceutically acceptable salt thereof, wherein X is a direct bond; Lis a direct bond; R₃ is

in which M is S; R₄ is H; R₁ is phenyl optionally substituted with oneor two fluoro; and R₂ is phenyl substituted with tert-butyl ortert-pentyl.

A twenty first embodiment of the present disclosure is a compoundselected from the group consisting of Compounds 1-1 to 1-37, Compounds2-1 to 2-4, Compounds 3-1 to 3-14, Compounds 4-1 to 4-4, Compounds 5-1to 5-108, and Compounds 6-1 to 6-61, which are listed in the followingTables 1 to 6.

The compounds of the present disclosure may contain asymmetric or chiralcenters, and exist in different stereoisomeric forms. Unless specifiedotherwise, all stereoisomeric forms of the compounds of the presentdisclosure as well as mixtures thereof, including racemic mixtures arewithin the scope of the present disclosure. In addition, the compoundsof the present disclosure may also exist in different geometric andpositional isomers. For example, both the cis- and trans-forms, as wellas mixtures of the compound with a double bond or a fused ring, are alsowithin the scope of the present disclosure.

Diastereomeric mixtures can be separated into their individualdiastereoisomers by any methods, such as by chromatography and/orfractional crystallization. Enantiomers can be separated by use of achiral HPLC column or by converting the enantiomeric mixture into adiastereomeric mixture by reaction with an appropriate optically activecompound to separate the diastereoisomers and convert the individualdiastereoisomers into pure enantiomers. The specific stereoisomers maybe synthesized by converting one stereoisomer into the other byasymmetric transformation, by using an optically active startingmaterial or by asymmetric synthesis using optically active reagents,catalysts, substrates or solvents.

Also within the present disclosure is a pharmaceutical composition,comprising: (1) the compound of the present disclosure or thepharmaceutically acceptable salt thereof; and (2) a pharmaceuticallyacceptable carrier, excipient or diluent. The composition may alsocomprise at least one additional pharmaceutical agent such asanti-cancer agents. The compound or the pharmaceutically acceptable saltthereof or the composition of the present disclosure may be used in themanufacture of a medicament of inhibiting the growth of tumor cells ortreating cancer.

Also within the present disclosure is a method for treating a cancer,which includes the step of administering to the subject in need thereofan effective amount of the compound of the present disclosure or thepharmaceutically acceptable salt thereof.

Further covered by the present disclosure a method of inhibiting agrowth of tumor cells, which includes the step of administering to asubject in need thereof an effective amount of the compound of thepresent disclosure or the pharmaceutically acceptable salt thereof.

In the present disclosure, the aforesaid subject can be mammal, forexample, human.

In the present disclosure, the compound of the present disclosure or thepharmaceutically acceptable salt thereof can inhibit the growth of tumorcells to achieve the purpose of treating a cancer. Examples of thecancer include, but are not limited to, gastric cancer, colon cancer,colorectal cancer, breast cancer, lung cancer, prostate cancer, bladdercancer, pancreatic cancer, liver cancer, uterine cancer, cervical caner,endometrial cancer, esophageal cancer, leukemia, lymphoma, kidneycancer, osteosarcoma, ovarian cancer, skin cancer, small intestinecancer, thymus cancer, thyroid cancer, nervous system cancers, bonecancer, brain cancer, or head and neck cancer.

The compounds or the pharmaceutically acceptable salt thereof of thepresent disclosure may be administered in combination with at least oneadditional pharmaceutical agent such as anti-cancer agent. Theadministration formulation can be, for example, (a) a single formulationcomprising the compound of the present disclosure or thepharmaceutically acceptable salt thereof, a pharmaceutically acceptablecarrier, excipient or diluent and at least one additional pharmaceuticalagent; or (b) two formulations administered simultaneously orsequentially and in any order, wherein one comprises the compound of thepresent disclosure or the pharmaceutically acceptable salt thereof, apharmaceutically acceptable carrier, excipient or diluent and the otherone comprises at least one additional pharmaceutical agent.

Suitable anti-cancer agents may include Herceptin, Rituximab, Docetaxel,Capecitabine, Cetuximab, Gefitinib, PD-1, Sorafenib tosylate orImatinib, but the present disclosure is not limited thereto. Any otheranti-cancer agents known in the art can also be used in the presentdisclosure.

Methods for synthesizing the compounds of formula (I) are well known inthe art. See, for example, R. Larock, Comprehensive OrganicTransformations (2^(nd) Ed., VCH Publishers 1999); P. G. M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis

(4^(th) Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieserand Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994);L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2^(nd)ed., John Wiley and Sons 2009); P. Roszkowski, J. K. Maurin, Z.Czarnocki “Enantioselective synthesis of (R)-(−)-praziquantel (PZQ)”Tetrahedron: Asymmetry 17 (2006) 1415-1419; and L. Hu, S. Magesh, L.Chen, T. Lewis, B. Munoz, L. Wang “Direct inhibitors of keapl-nrf2interaction as antioxidant inflammation modulators,” WO2013/067036.

The compounds of formula (I) thus prepared can be initially screenedusing in vitro assays, e.g., NCI-60 screening platform or MTS method.They can be subsequently evaluated using in vivo assays known in thefield. The selected compounds can be further tested to verify theirefficacy in disease related efficacy and adverse effects models. Basedon the results, an appropriate dosage range and administration route canbe determined.

The following embodiments are made to clearly exhibit theabove-mentioned and other technical contents, features and/or effects ofthe present disclosure. Through the exposition by means of the specificembodiments, people would further understand the technical means andeffects the present disclosure adopts to achieve the above-indicatedobjectives. Moreover, as the contents disclosed herein should be readilyunderstood and can be implemented by a person skilled in the art, allequivalent changes or modifications which do not depart from the conceptof the present disclosure should be encompassed by the appended claims.

EXAMPLE

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present disclosure toits fullest extent. The following specific examples, i.e., EXAMPLES 1-6,are therefore to be construed as merely illustrative, and not limitativeof the remainder of the disclosure in any way whatsoever. Allpublications cited herein are incorporated by reference in theirentirety.

Among the specific examples, EXAMPLES 1-6 set forth the procedures forpreparing certain intermediates and 228 exemplary compounds of formula(I), as well as the analytical data for the compounds thus prepared; andEXAMPLE 7 and EXAMPLE 8 set forth the protocols for testing thesecompounds.

Described below are the procedures used to synthesize the exemplarycompounds of the present disclosure.

Unless otherwise stated, all starting materials used were commerciallyavailable and used as supplied. Reactions requiring anhydrous conditionswere performed in flame-dried glassware and cooled under an argon ornitrogen atmosphere. Unless otherwise stated, reactions were carried outunder argon or nitrogen and monitored by analytical thin-layerchromatography performed on glass-backed plates (5 cm_10 cm) precoatedwith silica gel 60 F254 as supplied by Merck. Visualization of theresulting chromatograms was done by looking under an ultraviolet lamp(λ=254 nm), followed by dipping in an nBuOH solution of Ninhydrin (0.3%w/v) containing acetic acid (3% v/v) or ethanol solution ofphosphomolybdic acid (2.5% w/v) and caning by heat gun. Solvents forreactions were dried under an argon or nitrogen atmosphere prior to useas follows. THF, Toluene, and DCM were dried by the column of Driedmolecular Sieve 5A (LC technology solution Inc). DMF dried by calciumhydride or anhydrous is commercial available. Flash chromatography wasused routinely for purification and separation of product mixtures usingRediSep Rf Silica Gel Disposable Flash Columns, Gold® 20-40/40-60microns silica gel and Reusable Redi Sep Rf Gold® C18 Reversed Phasecolumns, 20-40 microns supplied by RediSep. Eluent systems are given involume/volume concentrations. ¹³C and ¹H NMR spectra were recorded onBruker AVIII (400 MHz). Chloroform-d or dimethyl sulfoxide-d6 and CD₃ODwas used as the solvent and TMS (δ 0.00 ppm) as an internal standard.Chemical shift values are reported in ppm relative to the TMS in delta(δ) units. Multiplicities are recorded as s (singlet), br s (broadsinglet), d (doublet), t (triplet), q (quartet), dd (doublet ofdoublet), dt (doublet of triplet), m (multiplet). Coupling constants (J)are expressed in Hz. Electrospray mass spectra (ESMS) were recordedusing a Thermo LTQ XL mass spectrometer. Spectral data were recorded asm/z values.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection may vary depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino protecting groups (NHPg) include, for example,acetyl, trifluoroacetyl, tbutoxycarbonyl (BOC),9-fluorenylmethyleneoxycarbonyl (Fmoc) and benzyloxycarbonyl (CBz).Similarly, a “hydroxyl protecting group” refers to a substituent of ahydroxy group that blocks or protects the hydroxy functionality.Suitable hydroxyl protecting groups (OPg) include, for example, allyl,acetyl, silyl, benzyl, paramethoxy benzyl, trityl, and the like. Theneed for such protection is readily determined by one skilled in theart.

Typical synthesis procedure of Compounds of EXAMPLE 1

Synthesis of 5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-amine

To a mixture of 3-ethoxybenzoic acid (2.38 g, 10 mmol) andthiosemicarbazide (1.37 g, 15 mmol) with 5 mL of phosphorus oxychloridewas refluxed gently for 2 hours. After cooling, 50 mL of water wasadded, and the mixture was refluxed for 7 hours and filtered,neutralized with 50% potassium hydroxide. The precipitate was washedwith water and recrystallized from ethanol to give titled compound (1.22g, 55%).

Synthesis of tert-butyl(6-(2-((5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate

To a mixture of 5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-amine (0.44 g, 2mmol) and HOBt (0.27 g, 2 mmol), EDCI (0.46 g, 2.4 mmol),2-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)acetic acid (0.74g, 2.4 mmol) in dry 12 mL DMF. The reaction was stirred overnight atroom temperature then added water. The precipitate was washed with waterand recrystallized from methanol to give titled compound (0.75 g, 73%).

Synthesis of2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

To a vigorous stirred solution of 2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide(0.75 g, 1.46 mmol) in anhydrous dichloromethane (15 mL) at roomtemperature, added trifluoroacetic acid (1.5 mL, 20 mmol) and stirredfor overnight. Excess trifluoroacetic acid was neutralized by addeddropwised of Na₂CO₃(aq) until pH=10. The precipitate was washed withwater and MeOH then further purified by silica gel flash columnchromatography using dichloromethane and methanol as eluent andconcentrated to give white solid (0.95 g, 65%).

Example 1: Compounds 1-1 to 1-37 Compound 1-12-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.88 (br. s., 1H), 7.61 (d, J=1.96 Hz,1H), 7.36-7.49 (m, 6H), 7.29 (d, J=7.82 Hz, 1H), 7.18 (dd, J=8.31, 1.96Hz, 1H), 7.02-7.10 (m, 1H), 4.10 (q, J=6.85 Hz, 2H), 3.84 (s, 2H), 1.35(t, J=6.85 Hz, 4H). MS (M+1): 412.

Compound 1-22-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.76 (s, 1H), 7.80-7.87 (m, 2H), 7.60 (d,J=1.96 Hz, 1H), 7.41 (s, 2H), 7.28 (d, J=8.31 Hz, 1H), 7.17 (dd, J=8.31,1.96 Hz, 1H), 7.02-7.10 (m, 2H), 4.09 (q, J=7.01 Hz, 2H), 3.83 (s, 2H),1.34 (t, J=7.09 Hz, 3H). MS (M+1): 412

Compound 1-32-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.61 (br. s., 1H), 8.26 (dd, J=8.1, 1.2Hz, 1H), 7.44-7.52 (m, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.10 (t, J=7.6 Hz,1H), 6.92 (s, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 5.98(s, 2H), 4.26 (q, J=6.8 Hz, 2H), 3.74 (s, 2H), 1.45 (t, J=6.8 Hz, 3H).MS (M+1):384.

Compound 1-42-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.01 (s, 1H), 8.04-8.08 (m, 1H), 7.82-7.89(m, 2H), 7.59-7.63 (m, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.15-7.21 (m, 2H),3.86 (s, 2H). MS (M+1):413

Compound 1-52-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.02 (s, 1H), 8.14 (d, J=7.8 Hz, 2H), 7.87(d, J=8.3 Hz, 3H), 7.65 (d, J=2.0 Hz, 1H), 7.60 (br. s., 2H), 7.32 (d,J=7.8 Hz, 1H), 3.88 (s, 2H). MS (M+1): 436.

Compound 1-62-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.69 (s, 1H), 8.26 (dd, J=7.8, 1.5 Hz,1H), 7.41 (td, J=7.6, 1.0 Hz, 2H), 7.22-7.33 (m, 2H), 7.07-7.22 (m, 2H),3.94-4.01 (m, 4H), 3.83 (s, 2H). MS (M+1): 398.

Compound 1-72-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.91 (s, 1H), 7.87 (d, J=8.3 Hz, 2H),7.68-7.76 (m, 2H), 7.60 (s, 1H), 7.42 (s, 2H), 7.28 (d, J=8.3 Hz, 1H),7.17 (d, J=7.8 Hz, 1H), 3.84 (s, 2H). MS (M+1): 446

Compound 1-82-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.06 (br. s., 1H), 8.31-8.41 (m, 2H),8.18-8.27 (m, 2H), 7.61 (d, J=1.5 Hz, 1H), 7.42 (s, 2H), 7.29 (d, J=8.3Hz, 1H), 7.18 (dd, J=8.3, 1.5 Hz, 1H), 3.86 (s, 2H). MS (M+1): 413.

Compound 1-92-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(dimethylamino)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (s, 1H), 7.68-7.74 (m, 2H), 7.60 (d,J=1.5 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.1,1.7 Hz, 1H), 6.75-6.81 (m, J=8.8 Hz, 2H), 3.81 (s, 2H), 2.98 (s, 6H). MS(M+1):411

Compound 1-102-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-propoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.66 (s, 1H), 8.28 (dd, J=7.8, 2.0 Hz,1H), 7.61 (d, J=1.5 Hz, 1H), 7.48 (td, J=7.8, 2.0 Hz, 1H), 7.43 (s, 2H),7.29 (d, J=8.3 Hz, 1H), 7.15-7.26 (m, 2H), 7.10 (t, J=7.6 Hz, 1H), 4.17(t, J=6.6 Hz, 2H), 3.83 (s, 2H), 1.79-1.92 (m, 2H), 1.06 (t, J=7.6 Hz,3H). MS (M+1):426.

Compound 1-112-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.95 (s, 1H), 8.27-8.33 (m, 1H), 7.67 (d,J=6.8 Hz, 1H), 7.56-7.64 (m, 3H), 7.42 (s, 2H), 7.26-7.32 (m, 1H), 7.19(d, J=2.0 Hz, 1H), 3.86 (s, 2H). MS (M+1): 452.

Compound 1-122-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.92 (br. s., 1H), 7.86-7.91 (m, 2H),7.69-7.73 (m, 2H), 7.60 (d, J=2.0 Hz, 1H), 7.43 (s, 2H), 7.28 (d, J=8.3Hz, 1H), 7.17 (dd, J=8.3, 1.5 Hz, 1H), 3.80-3.87 (m, 2H). MS (M+1):494

Compound 1-132-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromo-3-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.04 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.12(dd, J=8.3, 2.0 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H),7.46 (s, 2H), 7.29 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3, 2.0 Hz, 1H), 3.86(s, 2H). MS (M+1): 491.

Compound 1-142-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.80 (s, 1H), 7.86 (br. s., 2H), 7.76-7.85(m, 2H), 7.65 (d, J=1.5 Hz, 1H), 7.31 (dd, J=8.6, 4.6 Hz, 1H), 7.22 (dd,J=8.3, 1.5 Hz, 1H), 6.99-7.08 (m, 2H), 4.69 (spt, J=6.0 Hz, 1H), 3.84(s, 2H), 1.35 (s, 3H), 1.22 (s, 3H). MS (M+1):460

Compound 1-152-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (s, 1H), 8.28 (dd, J=8.0, 1.6 Hz,1H), 7.86 (br, 2H), 7.66 (d, J=1.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.32 (d,J=8.4 Hz, 1H), 7.26-7.21 (m, 2H), 7.10-7.06 (m, 1H), 4.90 (quin, J=6.0Hz, 1H), 3.85 (s, 2H), 1.37 (d, J=6.0 Hz, 6H). MS (M+1): 426.

Compound 1-162-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(pentan-3-yloxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.80 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.80(br. s., 2H), 7.64 (d, J=1.5 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.21 (dd,J=8.3, 1.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.32 (quin, J=5.7 Hz, 1H),3.84 (s, 2H), 1.56-1.72 (m, 2H), 0.90 (t, J=7.6 Hz, 3H). MS (M+1):454.

Compound 1-172-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-propoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.78 (br. s., 1H), 7.80-7.86 (m, J=8.8 Hz,2H), 7.64-7.68 (m, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.23 (dd, J=8.1, 1.2 Hz,1H), 7.02-7.08 (m, J=8.8 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 1.69-1.79 (m,2H), 1.51 (s, 2H), 0.98 (t, J=7.3 Hz, 3H). MS (M+1):440.

Compound 1-182-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.61 (s, 1H), 8.32 (br. s., 2H), 8.16 (d,J=8.8 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.27 (dd,J=8.1, 1.7 Hz, 1H), 6.65-6.75 (m, 2H), 4.24 (q, J=6.8 Hz, 2H), 4.11 (q,J=7.2 Hz, 2H), 3.85 (s, 2H), 1.43 (t, J=6.8 Hz, 3H), 1.34 (t, J=6.8 Hz,3H). MS (M+1): 456.

Compound 1-192-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.77 (s, 1H), 8.19 (br. s., 2H), 7.73 (d,J=8.8 Hz, 2H), 7.68 (s, 1H), 7.30-7.40 (m, 1H), 7.21-7.30 (m, 1H), 6.68(d, J=8.8 Hz, 2H), 3.85 (s, 2H). MS (M+1):384.

Compound 1-202-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-butoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.71 (s, 1H), 8.42 (br. s., 2H), 8.27 (dd,J=7.8, 2.0 Hz, 1H), 7.72 (s, 1H), 7.44-7.53 (m, 1H), 7.34-7.40 (m, 1H),7.27-7.34 (m, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 4.21(t, J=6.4 Hz, 2H), 3.87 (s, 2H), 1.77-1.88 (m, 2H), 1.52 (sxt, J=7.4 Hz,2H), 0.94 (t, J=7.6 Hz, 3H). MS (M+1):440.

Compound 1-212-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-butoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.81 (br. s., 1H), 11.71 (br. s., 1H),7.88 (s, 1H), 7.80-7.85 (m, J=8.8 Hz, 2H), 7.63 (d, J=8.3 Hz, 1H), 7.36(dd, J=8.3, 1.5 Hz, 1H), 7.01-7.07 (m, J=8.8 Hz, 2H), 4.02 (t, J=6.6 Hz,2H), 3.93 (s, 1H), 1.51 (s, 7H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1):440.

Compound 1-222-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(pentan-3-yloxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.71 (br. s., 1H), 9.15 (br. s., 2H), 8.29(dd, J=7.8, 1.5 Hz, 1H), 7.79 (s, 1H), 7.41-7.48 (m, 2H), 7.33-7.39 (m,1H), 7.24 (d, J=8.3 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 4.58 (t, J=5.6 Hz,1H), 3.90 (s, 2H), 1.67-1.76 (m, 4H), 0.89 (t, J=7.3 Hz, 6H). MS(M+1):454

Compound 1-232-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-butoxy-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.57 (s, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.79(br. s., 2H), 7.65 (d, J=1.5 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (dd,J=8.3, 1.5 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.6, 2.2 Hz,1H), 4.19 (t, J=6.6 Hz, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.83 (s, 2H),1.75-1.88 (m, 2H), 1.47-1.56 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 0.94 (t,J=7.6 Hz, 3H). MS (M+1):484.

Compound 1-242-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4,6-triethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 7.59 (d, J=1.5 Hz, 1H), 7.38 (s, 2H), 7.27(d, J=8.3 Hz, 1H), 7.16 (dd, J=8.3, 1.5 Hz, 1H), 6.28 (s, 2H), 4.08 (q,J=1.0 Hz, 2H), 3.99 (q, J=1.0 Hz, 4H), 3.75 (s, 2H), 1.33 (t, J=1.0 Hz,4H), 1.17 (t, J=1.0 Hz, 6H).

MS (M+1): 500.

Compound 1-252-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxypyridin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.87 (br s, 1H), 8.60 (s, 1H), 8.34 (d,J=4.8 Hz, 1H), 8.16 (d, J=4.8 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.42 (s,2H), 7.29 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 1.6 Hz, 1H), 4.40 (q,J=6.8 Hz, 2H), 3.84 (s, 2H), 1.46 (t, J=6.8 Hz, 3H). MS (M+1):413.

Compound 1-262-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(ethoxymethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.61 (br s, 1H), 8.17 (d, J=9.2 Hz, 1H),7.60 (d, J=1.2 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.17 (dd,J=9.2, 1.6 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.74 (dd, J=8.8, 2.8 Hz,1H), 5.45 (s, 2H), 4.09 (q, J=6.8 Hz, 2H), 3.81 (s, 2H), 3.68 (q, J=6.8Hz, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H). MS (M+1):486.

Compound 1-272-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.53 (br s, 1H), 8.15 (d, J=8.8 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.17 (dd,J=8.4, 2.0 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.68 (dd, J=8.8, 2.4 Hz,1H), 4.25 (t, J=5.6 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.80 (s, 2H), 2.77(t, J=5.6 Hz, 2H), 2.24-2.20 (m, 4H), 2.06 (s, 3H), 1.35 (t, J=6.8 Hz,3H). MS (M+1):554.

Compound 1-282-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(3-(dimethylamino)propoxy)-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.57 (br s, 1H), 8.15 (d, J=8.8 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.17 (dd,J=8.0, 1.6 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.8, 2.4 Hz,1H), 4.21 (t, J=6.4 Hz, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.81 (s, 2H), 2.46(t, J=6.8 Hz, 2H), 2.13 (s, 6H), 1.95 (quin, J=6.8 Hz, 2H), 1.34 (t,J=6.8 Hz, 3H). MS (M+1):513.

Compound 1-292-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(2-(dimethylamino)ethoxy)-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.55 (br s, 1H), 8.16 (d, J=8.4 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd,J=8.4, 1.2 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.8, 2.4 Hz,1H), 4.26 (t, J=6.0 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.81 (s, 2H), 2.76(t, J=6.0 Hz, 2H), 2.25 (s, 6H), 1.35 (t, J=6.0 Hz, 3H). MS (M+1):499.

Compound 1-302-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(5-ethoxypyridin-2-yl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (br s, 1H), 8.16 (d, J=8.4 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd,J=8.4, 1.2 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.8, 2.4 Hz,1H), 4.26 (t, J=6.0 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.81 (s, 2H), 2.76(t, J=6.0 Hz, 2H), 2.25 (s, 6H), 1.35 (t, J=6.0 Hz, 3H). MS (M+1):413.

Compound 1-312-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-(2-(dimethylamino)ethoxy)pyridin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.84 (br s, 1H), 8.65 (s, 1H), 8.35 (d,J=5.2 Hz, 1H), 8.16 (d, J=4.8 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.43 (s,2H), 7.29 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 4.42 (t,J=5.6 Hz, 2H), 3.85 (s, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.24 (s, 6H). MS(M+1):456.

Compound 1-322-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-methoxyethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.54 (br s, 1H), 8.16 (d, J=8.8 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.41 (br s, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.18(dd, J=8.0, 1.6 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.69 (dd, J=8.8, 2.4Hz, 1H), 4.30-4.32 (m, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H),3.77-3.75 (m, 2H), 3.34 (s, 3H), 1.35 (t, J=7.4 Hz, 3H). MS (M+1):486.

Compound 1-332-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-propylphenyl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.82 (s, 1H), 7.78-7.86 (m, 2H), 7.60 (d,J=1.5 Hz, 1H), 7.42 (s, 2H), 7.32-7.38 (m, J=8.3 Hz, 2H), 7.28 (d, J=7.8Hz, 1H), 7.17 (dd, J=8.1, 1.7 Hz, 1H), 3.83 (s, 2H), 2.61 (t, J=7.6 Hz,2H), 1.57-1.70 (m, 2H), 0.90 (t, J=7.3 Hz, 3H). MS (M+1):410.

Compound 1-342-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.77 (br, 1H), 9.19 (s, 1H), 8.49 (d,J=6.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.40 (br, 2H), 7.29 (d, J=8.4 Hz,1H), 7.24 (d, J=6.0 Hz, 1H), 7.17 (dd, J=8.4, 2.0 Hz, 1H), 4.32 (q,J=6.8 Hz, 2H), 3.83 (s, 2H), 1.42 (t, J=6.8 Hz, 3H). MS (M+1):413.

Compound 1-352-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4,6-diethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.71 (br, 1H), 8.84 (s, 1H), 7.60 (d,J=1.2 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4,1.6 Hz, 1H), 6.57 (s, 1H), 4.36 (q, J=6.8 Hz, 2H), 4.29 (q, J=6.8 Hz,2H), 3.82 (s, 2H), 1.42 (t, J=6.8 Hz, 3H), 1.32 (t, J=6.8 Hz, 3H). MS(M+1): 457.

Compound 1-362-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1,3,4-thiadiazol-2-yl)-N-methylacetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.79 (br s, 1H), 8.16 (d, J=8.4 Hz, 1H),7.60 (d, J=1.6 Hz, 1H), 7.42 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd,J=8.4, 1.2 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.68 (dd, J=8.8, 2.4 Hz,1H), 4.26 (t, J=6.0 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.81 (s, 2H), 2.76(t, J=6.0 Hz, 2H), 2.25 (s, 6H), 1.35 (t, J=6.0 Hz, 3H). MS (M+1):470.

Compound 1-372-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4,6-diethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)-N-methylacetamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 7.55 (s, 1H), 7.43 (s, 2H),7.30 (d, J=8.0 Hz, 1H), 7.12 (dd, J=8.4, 1.6 Hz, 1H), 6.56 (s, 1H), 4.36(q, J=6.8 Hz, 2H), 4.28 (q, J=6.8 Hz, 2H), 4.16 (s, 2H), 3.81 (s, 3H),1.40 (t, J=6.8 Hz, 3H), 1.32 (t, J=6.8 Hz, 3H). MS (M+1): 471.

Typical synthesis procedure of Compounds of EXAMPLE 2

Step 1: Synthesis of 4-ethoxybenzylidene hydrazinecarboxamides

Semicarbazide hydrochloride (1.11 g, 10 mmol) and sodium acetate (1.64g, 20 mmol) were dissolved in 15-20 ml of distilled water in aflat-bottomed flask. 4-ethoxybenzaldehyde (1.5 g, 10 mmol) was dissolvedin ethanol. This solution was added slowly to the solution ofsemicarbazide hydrochloride. The precipitate was filtered, dried, andrecrystallized from hot ethanol (95%) to obtain 4-ethoxybenzylidenehydrazinecarboxamide.

Step 2: Synthesis of 4-ethoxyphenyl-1,3,4-Oxadiazol-2-amines

Sodium acetate (20 mmol) and 4-ethoxybenzylidene hydrazinecarboxamide(2.1 g, 10 mmol) were dissolved in 30-40 ml of glacial acetic acid withcontinuous stirring. Bromine (0.7 ml in 5 ml of glacial acetic acid) wasadded slowly. Solution was stirred for 1 h and poured on crushed ice.The resulting solid was separated, dried, and recrystallized from hotethanol (95%) to afford 4-ethoxyphenyl-1,3,4-oxadiazol-2-amines.

Synthesis of tert-butyl(6-(2-((5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate

To a mixture of 4-ethoxyphenyl-1,3,4-oxadiazol-2-amines (0.41 g, 2 mmol)and HOBt (0.27 g, 2 mmol), EDCI (0.46 g, 2.4 mmol),2-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)acetic acid (0.74g, 2.4 mmol) in dry 12 mL DMF. The reaction was stirred overnight atroom temperature then added water. The precipitate was washed with waterand recrystallized from methanol to give tert-butyl(6-(2-((5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate(0.74 g, 75%).

Synthesis of2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide

To a vigorous stirred solution of tert-butyl(6-(2-((5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate(0.74 g, 1.50 mmol) in anhydrous dichloromethane (15 mL) at roomtemperature, added trifluoroacetic acid (1.5 mL, 20 mmol) and stirredfor overnight. Excess trifluoroacetic acid was neutralized by addeddropwised of Na₂CO₃(aq) until pH=10. The precipitate was washed withwater and MeOH then further purified by silica gel flash columnchromatography using dichloromethane and methanol as eluent andconcentrated to give white solid. (0.35 g, 60%)

Example 2: Compounds 2-1 to 2-4 Compound 2-12-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 11.87 (br. s., 1H), 7.99-8.07 (m, 1H),7.79-7.86 (m, 2H), 7.67-7.74 (m, 5H), 7.59 (d, J=1.0 Hz, 1H), 7.42 (s,2H), 7.28 (d, J=8.3 Hz, 1H), 7.12-7.20 (m, 3H), 4.09 (q, J=7.01 Hz, 2H),3.76 (s, 2H), 1.34 (t, J=7.09 Hz, 4H). MS (M+1): 356.

Compound 2-22-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 11.89 (br. s., 1H), 8.04 (br. s., 1H),7.71-7.74 (m, 1H), 7.55 (ddd, J=8.6, 7.3, 1.7 Hz, 1H), 7.33 (d, J=7.8Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 2H), 7.06-7.11 (m, 2H), 4.14 (q, J=1.0Hz, 2H), 3.80 (s, 2H), 1.33 (t, J=1.0 Hz, 3H). MS (M+1): 396.

Compound 2-32-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-propoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (br. s., 1H), 7.73 (dd, J=7.8, 2.0Hz, 1H), 7.50-7.62 (m, 1H), 7.40 (s, 2H), 7.18-7.32 (m, 2H), 7.16 (dd,J=8.1, 1.7 Hz, 1H), 7.05-7.12 (m, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.76 (s,2H), 1.65-1.77 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). MS (M+1): 410.

Compound 2-42-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 7.61-7.71 (m, 2H), 7.49-7.55(m, 2H), 7.40 (s, 2H), 7.25 (d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 2.0 Hz,1H), 3.54 (s, 2H). MS (M+1): 436.

Typical synthesis procedure of Compounds of EXAMPLE 3 and EXAMPLE 4

Synthesis of 2-bromo-2-(3-nitrophenyl)-1-(p-tolyl)ethan-1-one

2-(3-nitrophenyl)-1-(p-tolyl)ethan-1-one (25.5 g, 100 mmol) and AlCl₃(30 mg, 0.23 mmol) were dissolved in 20 mL CHCl₃. Bromine (22 g, 120mmol) in 100 mL CHCl₃ was then added dropwise by addition funnel at 0°C. by ice bath. The reaction was stirred at rt for 2 h and thenextraction dried with Na₂SO₄ and concentrated under reduced pressure.The crude reaction mixture was directly purified by flash chromatographyon silica gel (DCM/hexanes to 5:1). The title compound was isolated toobtain white solid (30.0 g, 89%).

Synthesis of 5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-amine

This compound was prepared from refluxing of a solution of2-bromo-2-(3-nitrophenyl)-1-(p-tolyl)ethan-1-one (16.7 g, 50 mmol) inethanol (30 ml) and thiourea (4.28 g, 55 mmol) for 1 h. The reaction waswork up by 100 mL of Na₂CO_(3(sat)). The crude product was filtered andwashed with water to neutrality and then was recrystallized from ethanolto obtain pale yellow crystals (7.78 g, 80%).

Synthesis of tert-butyl(6-(2-((5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate

To a mixture of 5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-amine (0.62 g, 2mmol), 2-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl) aceticacid (0.62 g, 2 mmol), EDCI (0.76 g, 4 mmol), and HOBt (0.54 g, 4 mmol)in dry 20 mL DCM. The reaction was stirred at room temperature overnightthen added water and extracted with DCM and concentrated got a cruderesidue. Purification of the crude residue by column chromatography withEtOAc/hexane (0:100-30:70) as the eluent and concentrated to affordorange solid (0.84 g, 70%).

Synthesis of2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide

To a vigorous stirred solution oftert-butyl(6-(2-((5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate(0.84 g, 1.40 mmol) in anhydrous dichloromethane (15 mL) at roomtemperature, added trifluoroacetic acid (1.5 mL, 20 mmol) and stirredovernight. Excess trifluoroacetic acid was neutralized by dropwisedaddition of Na₂CO₃(aq) until pH=10. The precipitate was washed withwater and MeOH then further purified by silica gel flash columnchromatography using dichloromethane and methanol as eluent andconcentrated to give white solid (0.45 g, 64%).

Example 3: Compounds 3-1 to 3-14 Compound 3-12-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.68 (s, 1H), 8.16 (dt, J=7.1, 1.3 Hz,1H), 8.06 (t, J=2.0 Hz, 1H), 7.61-7.75 (m, 4H), 7.31 (t, J=7.8 Hz, 3H),7.20 (dd, J=8.3, 1.5 Hz, 1H), 7.15 (d, J=8.3 Hz, 2H), 3.81 (s, 2H), 2.30(s, 3H). MS (M+1):440.

Compound 3-22-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-bromophenyl)-5-phenylthiazol-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃): δ 9.09 (br. s., 1H), 7.49-7.57 (m, 2H),7.32-7.39 (m, 2H), 7.25-7.32 (m, 7H), 7.20 (d, J=7.8 Hz, 1H), 5.29 (br.s., 2H), 3.81 (s, 2H). MS (M+1): 521.

Compound 3-32-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.61 (s, 1H), 8.16 (br. s., 2H), 7.68 (d,J=1.5 Hz, 1H), 7.53-7.59 (m, 2H), 7.28-7.38 (m, 3H), 7.19-7.28 (m, 3H),7.14 (d, J=8.3 Hz, 2H), 3.81 (s, 2H), 2.29 (s, 3H). MS (M+1): 535.

Compound 3-42-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-fluorophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.57 (s, 1H), 8.18 (br. s., 2H), 7.26-7.41(m, 6H), 7.15-7.26 (m, 3H), 7.06-7.15 (m, 2H), 3.81 (s, 2H), 2.28 (s,3H). MS (M+1):475.

Compound 3-52-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3,4-dimethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.49 (s, 1H), 8.39 (br. s., 2H), 7.71 (d,J=1.0 Hz, 1H), 7.31-7.41 (m, 3H), 7.25-7.31 (m, 1H), 7.09-7.16 (m, 2H),6.91-6.99 (m, 1H), 6.78-6.87 (m, 2H), 3.82 (s, 2H), 3.76 (s, 3H), 3.58(s, 3H), 2.28 (s, 3H). MS (M+1): 517.

Compound 3-62-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-fluorophenyl)-4-(4-propoxyphenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.53 (s, 1H), 7.92 (br. s., 2H), 7.66 (s,1H), 7.29-7.38 (m, 5H), 7.14-7.29 (m, 3H), 6.81-6.91 (m, 2H), 3.91 (t,J=6.6 Hz, 3H), 3.80 (s, 2H), 1.65-1.76 (m, 2H), 0.96 (t, J=7.3 Hz, 3H).MS (M+1): 519.

Compound 3-72-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(p-tolyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃): δ 9.39 (br. s., 1H), 7.71 (s, 3H), 7.50-7.54(m, 2H), 7.17-7.23 (m, 3H), 7.08 (d, J=7.8 Hz, 2H), 5.28 (d, J=10.8 Hz,2H), 3.80 (s, 2H), 2.31 (s, 3H). MS (M+1): 593.

Compound 3-82-(2-aminobenzo[d]thiazol-6-yl)-N-(5-bromo-4-(3-methoxyphenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, CDCl₃): δ 9.14 (br. s., 1H), 7.49-7.56 (m, 2H),7.34-7.38 (m, 1H), 7.30-7.34 (m, 1H), 7.26-7.30 (m, 1H), 7.20 (dd,J=8.3, 2.0 Hz, 1H), 6.88 (ddd, J=8.2, 2.6, 1.0 Hz, 1H), 5.28 (br. s.,2H), 3.81 (s, 2H), 3.80 (s, 3H). MS (M+1): 475.

Compound 3-92-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-ethoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.51 (s, 1H), 7.98 (br. s., 2H), 7.63-7.69(m, 1H), 7.28-7.37 (m, 5H), 7.16-7.28 (m, 3H), 6.80-6.90 (m, 2H), 4.01(q, J=7.2 Hz, 2H), 3.80 (s, 2H), 1.31 (t, J=7.1 Hz, 3H). MS (M+1):505.

Compound 3-102-(2-aminobenzo[d]thiazol-6-yl)-N-(4,5-bis(4-bromophenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.59 (s, 1H), 7.52-7.61 (m, 5H), 7.40 (s,2H), 7.33-7.38 (m, 2H), 7.21-7.32 (m, 3H), 7.17 (dd, J=8.1, 1.7 Hz, 1H),3.79 (s, 2H). MS (M+1): 599.

Compound 3-112-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (s, 1H), 7.58 (d, J=1.5 Hz, 1H),7.44-7.49 (m, 2H), 7.40 (s, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.16 (dd,J=8.3, 2.0 Hz, 1H), 6.92-6.98 (m, 3H), 6.86-6.90 (m, 1H), 4.03 (q, J=6.8Hz, 2H), 3.74 (s, 2H), 1.32 (t, J=6.8 Hz, 3H). MS (M+1):411.

Compound 3-122-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(2,4-diethoxyphenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.60(m, 1H), 7.48 (s, 1H), 7.41 (br s, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.17(dd, J=8.4, 1.6 Hz, 1H), 6.61-6.58 (m, 2H), 4.13 (q, J=6.8 Hz, 2H), 4.06(q, J=6.8 Hz, 2H), 3.76 (s, 2H), 1.43 (t, J=6.8 Hz, 3H), 1.33 (t, J=6.8Hz, 3H). MS (M+1):455

Compound 3-132-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.44 (s, 1H), 7.77-7.74 (m, 2H), 7.59 (d,J=2.0 Hz, 1H), 7.43 (s, 2H), 7.38-7.34 (m, 2H), 7.28 (d, J=2.0 Hz, 1H),7.18-7.08 (m, 4H), 6.95-6.92 (m, 2H), 4.01 (q, J=6.8 Hz, 2H), 3.75 (s,2H), 1.30 (t, J=6.8 Hz, 3H).

LCMS, [M+1]⁺: 503.

Compound 3-142-(2-aminobenzo[d]thiazol-6-yl)-N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.29 (s, 1H), 7.47-7.59 (m, 3H), 7.41 (s,2H), 7.23-7.34 (m, 3H), 7.10-7.23 (m, 5H), 6.93-7.01 (m, 2H), 4.17 (s,2H), 4.04 (q, J=7.0 Hz, 2H), 3.71 (s, 2H), 1.32 (t, J=7.1 Hz, 3H). LCMS[M+1]⁺:501.

Example 4: Compounds 4-1 to 4-4 Compound 4-1

¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (br. s., 1H), 8.97 (br. s., 1H), 7.88(br. s., 1H), 7.75-7.84 (m, J=8.8 Hz, 2H), 7.37 (br. s., 2H), 7.26 (q,J=8.3 Hz, 2H), 7.00-7.10 (m, J=8.8 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 1.34(t, J=6.8 Hz, 3H). MS (M+1): 413.

Compound 4-2

¹H NMR (400 MHz, DMSO-d₆): δ 11.36 (s, 1H), 7.92 (br. s., 2H), 7.64 (d,J=1.5 Hz, 1H), 7.42-7.48 (m, 2H), 7.32 (d, J=8.3 Hz, 1H), 7.21 (dd,J=8.3, 2.0 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 6.90-6.93 (m, 2H), 6.64 (d,J=3.9 Hz, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.68 (s, 2H), 1.31 (t, J=6.8 Hz,3H). MS (M+1):410.

Compound 4-3

¹H NMR (400 MHz, DMSO-d₆): δ 11.53 (br s, 1H), 7.74 (d, J=8.0 Hz, 1H),7.62 (d, J=2.0 Hz, 1H), 7.53 (br s, 2H), 7.27-7.30 (m, 2H), 7.19 (dd,J=8.0, 1.6 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.57 (dd, J=8.0, 2.0 Hz,1H), 4.19-4.17 (m, 2H), 4.04 (q, J=6.8 Hz, 2H), 3.75-7.32 (m, 2H), 3.71(s, 2H), 3.31 (s, 3H), 1.32 (t, J=6.8 Hz, 3H). MS (M+1): 468.

Compound 4-4

¹H NMR (400 MHz, DMSO-d₆): δ 11.41 (s, 1H), 11.35 (s, 1H), 7.84 (d,J=8.4 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.40 (br s, 2H), 7.27 (d, J=8.4Hz, 1H), 7.19-7.15 (m, 2H), 6.54 (s, 1H), 4.09 (q, J=6.8 Hz, 2H), 4.02(q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.41 (t, J=6.8 Hz, 3H), 1.32 (t, J=6.8Hz, 3H). MS (M+1):438.

Typical synthesis procedure of Compounds of EXAMPLE 5

Synthesis of 1-(4-Ethoxy-phenyl)-ethanone

1-(4-ethoxyphenyl)ethan-1-one

K₂CO₃ (20.73 g, 150 mmol) was added to a solution of1-(4-hydroxy-phenyl)-ethanone (13.62 g, 100 mmol) in MeCN (200 ml) underconstant stirring. Ethyl bromide (23.4 g, 150 mmol) was added and thereaction mixture is heated at 80° C. for 20 hours. Water (100 ml) isadded and the reaction mixture is extracted with EtOAc. The organicphase is washed with brine, dried (Na₂SO₄) and concentrated in vacuum.The crude residues was purified by column chromatography withEtOAc/hexane (0:100-5:95) as the eluent. Yield (14.43 g, 88%). LCMS:MH⁺165.

Synthesis of 2-Bromo-1-(4-ethoxyphenyl)ethanone

2-bromo-1-(4-ethoxyphenyl)ethan-1-one

To a solution of NBS (16.5 g, 91 mmol), PTSA:hydrate (27 g, 142 mmole),1-(4-ethoxy-phenyl)-ethanone (11.6 g, 71 mmol) in ACN (348 ml) and theresulting mixture are stirred at 82° C. reflux room temperature for 2hours. Then removed ACN and added Water (400 ml) extracted with EtOAc(450 ml). The organic phase is washed with brine, dried (Na₂SO₄) andconcentrated in vacuum, and the obtained crude product (17.5 g, yield99%) could be employed in further process steps without furtherpurification.

Synthesis of 4-(4-ethoxyphenyl)thiazol-2-amine

4-(4-ethoxyphenyl)thiazol-2-amine

To a mixture of thiourea (6.58 g) and2-bromo-1-(4-ethoxyphenyl)ethan-1-one (17.50 g) was added ethanol (90mL). The reaction mixture was heated up to reflux for 2.5 hours. Thereaction was cooled down to RT. Ethanol was removed under vacuum toafford the residue as a brown solid. The mixture was obtained by washedwith 100 ml water and 50 ml saturated sodium bicarbonate until yellowcolor was observed in the aqueous phase. The mixture was suction toremoved water then washed cake by 50 ml water. The crude product wasslurry by 75 ml hot EtOH for 2 h then removed 40 ml EtOH by distilledand solution cooled to RT then suction to afford the solid powder4-(4-ethoxyphenyl)thiazol-2-amine 15.84 g. MS (ES⁺) m/z 221 (MH⁺).

Synthesis of 5-bromo-4-(4-ethoxyphenyl)thiazol-2-amine

To a solution of N-bromosuccinimide (4.84 g, 27.2 mmol) in Acetone (200mL) was added over 30 min to a solution of4-(4-ethoxyphenyl)thiazol-2-amine (5.00 g, 22.7 mmol) in Acetone (200mL) at 0° C. by ice bath. After 1 h, the reaction was concentrated invacuo, then the residue was extraction with EA (100 mL) and sodiumthiosulfate aqueous two times. The combination of organic solvent werewashed with brine, dried and evaporated, which was sufficiently pure touse directly. 5-bromo-4-(4-ethoxyphenyl)thiazol-2-amine (6.31 g, 93%).MS (ES⁺) m/z 299 (MH⁺)

Synthesis of 4-(4-ethoxyphenyl)-5-phenoxythiazol-2-amine

4-(4-ethoxyphenyl)-5-phenoxythiazol-2-amine

To a mixture of 5-bromo-4-(4-ethoxyphenyl)thiazol-2-amine (3.1 g, 10.4mmol), phenol (1.27 g, 13.5 mmol) and cesium carbonate (4.40 g, 13.5mmol) was added acetone (100 mL). The reaction mixture was heated to 50°C. and stirred for 10 hours. Solvent was removed. The crude product waspurified by flash chromatography (EtOAc:PE=0:1 to 1:4) to afford4-(4-ethoxyphenyl)-5-phenoxythiazol-2-amine. 2.23 g. MS (ES⁺) m/z 313(MH⁺).

Synthesis ofN-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

To a solution of 5-nitrothiophene-2-carboxylic acid (1.71 g, 10 mmol),4-(4-ethoxyphenyl)-5-phenoxythiazol-2-amine (3.12 g, 10 mmol), EDCl(3.83 g, 20 mmol) and HOBt (2.70 g, 20 mmol) in DCM (50 mL) were stirredat room temperature for overnight. Extraction and remove solvent. Thecrude product was purified by flash chromatography (DCM:EtOAc=1:0 to4:1) to affordN-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamideas red solid. Yield: 4.22 g, 90%.

Example 5: Compounds 5-1 to 5-108 Compound 5-1N-(4-(4-bromophenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 9.69 (br, 1H), 7.85 (d, J=4.4 Hz, 1H),7.75-7.72 (m, 2H), 7.51 (d, J=4.4 Hz, 1H), 7.48-7.44 (m, 2H), 7.36-7.31(m, 2H), 7.16-7.09 (m, 3H). MS (M+1): 502.

Compound 5-2N-(4-(4-bromophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.57 (br, 1H), 7.89 (d, J=4.4 Hz, 1H),7.74-7.71 (m, 2H), 7.58 (d, J=4.4 Hz, 1H), 7.50-7.47 (m, 2H), 7.22-7.17(m, 2H), 7.12-7.09 (m, 2H). MS (M+1): 586.

Compound 5-35-nitro-N-(4-(3-nitrophenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.63 (br, 1H), 8.82 (s, 1H), 8.25 (d, J=8.0Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 7.66 (d, J=4.4Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.19-7.14 (m, 3H).MS (M+1): 469.

Compound 5-4N-(4-(3-methoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.85 (br, 1H), 7.72 (d, J=4.4 Hz, 1H), 7.45(d, J=4.4 Hz, 1H), 7.38-7.31 (m, 4H), 7.23-7.19 (m, 1H), 7.14-7.11 (m,3H), 6.77-6.74 (m, 1H), 3.71 (s, 3H). MS (M+1): 454.

Compound 5-5N-(4-(2-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.44 (br s, 1H), 7.72 (d, J=4.4 Hz, 1H),7.62 (dd, J=8.0, 1.6 Hz, 1H), 7.53 (d, J=4.4 Hz, 1H), 7.34-7.29 (m, 2H),7.25-7.21 (m, 1H), 7.13-7.08 (m, 3H), 6.92-6.86 (m, 2H), 4.08 (q, J=6.8Hz, 2H), 1.40 (t, J=6.8 Hz, 3H). MS (M+1): 468.

Compound 5-6N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.03 (br. s, 1H), 7.71 (d, J=4.4 Hz, 1H),7.68-7.65 (m, 2H), 7.49 (d, J=4.4 Hz, 1H), 7.35-7.30 (m, 2H), 7.13-7.09(m, 3H), 6.82-6.78 (m, 2H), 3.97 (q, J=6.8 Hz, 2H), 1.37 (t, J=6.8 Hz,3H). MS (M+1):468.

Compound 5-7N-(4-(4-bromophenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.87 (br. s, 1H), 7.86 (d, J=4.4 Hz, 1H),7.69-7.66 (m, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.57 (d, J=4.4 Hz, 1H),7.48-7.45 (m, 2H), 7.17 (d, J=8.4 Hz, 2H), 1.22 (s, 9H). MS (M+1):570.

Compound 5-85-nitro-N-(4-(4-propoxyphenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.59 (br. s, 1H), 7.70 (d, J=4.4 Hz, 1H),7.67-7.63 (m, 2H), 7.39 (d, J=4.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H),7.12-7.08 (m, 2H), 6.83-6.79 (m, 2H), 3.86 (q, J=6.8 Hz, 2H), 1.77 (sex,J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). MS (M+1): 570.

Compound 5-95-nitro-N-(5-phenoxy-4-(4-propoxyphenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.32 (br. s., 1H), 8.17-8.27 (m, 2H),7.77-7.83 (m, J=8.8 Hz, 2H), 7.37-7.43 (m, 2H), 7.13-7.19 (m, 3H),6.94-6.99 (m, 2H), 3.92 (t, J=6.6 Hz, 2H), 1.66-1.76 (m, 2H), 0.96 (t,J=7.3 Hz, 3H). MS (M+1):482.

Compound 5-10N-(4-(4-isopropoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.33 (br. s., 1H), 8.18-8.26 (m, 2H), 7.80(d, J=8.8 Hz, 2H), 7.37-7.44 (m, 2H), 7.14-7.19 (m, 3H), 6.95 (d, J=9.3Hz, 2H), 4.61 (spt, J=6.0 Hz, 1H), 1.25 (d, J=5.9 Hz, 6H). MS (M+1): 482

Compound 5-11N-(4-(4-bromophenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.45 (br. s., 1H), 8.22-8.25 (m, 1H),8.19-8.22 (m, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 4H),7.53-7.58 (m, 2H), 7.47-7.51 (m, 1H). MS (M+1): 570

Compound 5-12N-(4-(2,4-diethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.68 (br, 1H), 7.67 (d, J=4.4 Hz, 1H),7.48-7.45 (m, 2H), 7.33-7.28 (m, 2H), 7.12-7.06 (m, 3H), 6.38-6.34 (m,2H), 4.00 (q, J=7.2 Hz, 2H), 3.95 (q, J=7.2 Hz, 2H), 1.39-1.34 (m, 6H).MS (M+1): 512.

Compound 5-135-nitro-N-(4-(4-propoxyphenyl)-5-(pyridin-3-yloxy)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.38 (br. s., 1H), 8.53 (d, J=2.9 Hz, 1H),8.35-8.40 (m, 1H), 8.18-8.25 (m, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.56 (ddd,J=8.6, 2.9, 1.2 Hz, 1H), 7.42 (dd, J=8.6, 4.6 Hz, 1H), 6.97 (d, J=8.8Hz, 2H), 3.92 (t, J=6.6 Hz, 2H), 1.66-1.76 (m, 2H), 0.96 (t, J=7.3 Hz,3H). MS (M+1):483

Compound 5-14N-(4-(4-(tert-butyl)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.37 (br. s., 1H), 8.22 (br. s., 2H), 7.84(d, J=8.3 Hz, 2H), 7.38-7.48 (m, 4H), 7.19 (br. s., 3H), 1.27 (br. s.,9H). MS (M+1): 480.

Compound 5-15 N-(4-(4-(2-m ethoxyethoxy)phenyl)-5-(pyri din-3-yloxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.39 (br, 1H), 8.54 (d, J=2.8 Hz, 1H),8.39-8.37 (m, 1H), 8.23-8.20 (m, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.59-7.55(m, 1H), 7.44-7.41 (m, 1H), 7.02-6.98 (m, 2H), 4.11-4.08 (m, 2H),3.65-3.63 (m, 2H), 3.29 (s, 3H). MS (M+1): 499.

Compound 5-16N-(4-(4-(2-methoxyethoxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.35 (br, 1H), 7.74 (d, J=4.0 Hz, 1H),7.72-7.69 (m, 2H), 7.43 (d, J=4.4 Hz, 1H), 7.34-7.30 (m, 2H), 7.13-7.10(m, 3H), 6.87-6.84 (m, 2H), 4.08-4.06 (m, 2H), 3.73-3.70 (m, 2H), 3.42(s, 3H). MS (M+1): 498.

Compound 5-175-nitro-N-(4-(4-propoxyphenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.39 (br. s., 1H), 8.18-8.26 (m, 2H),7.75-7.81 (m, J=8.8 Hz, 2H), 7.60-7.66 (m, 1H), 7.48-7.55 (m, 2H), 7.45(dd, J=8.3, 2.0 Hz, 1H), 6.93-6.99 (m, J=9.3 Hz, 2H), 3.92 (t, J=6.6 Hz,2H), 1.70 (sxt, J=7.1 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H). MS (M+1):550

Compound 5-18N-(4-(4-bromophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.42 (br. s., 1H), 8.23 (s, 1H), 8.18-8.21(m, 1H), 7.79-7.84 (m, 2H), 7.61-7.66 (m, 2H), 7.38-7.44 (m, 2H),7.29-7.33 (m, 2H). MS (M+1): 585

Compound 5-19N-(4-(4-bromophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.50 (br. s., 1H), 8.19-8.26 (m, 2H),7.77-7.86 (m, 3H), 7.63-7.69 (m, 3H), 7.38 (t, J=7.6 Hz, 1H), 7.30 (d,J=8.3 Hz, 1H). MS (M+1): 569. 571

Compound 5-20N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.36 (br. s., 1H), 8.16-8.29 (m, 2H),7.79-7.86 (m, J=8.3 Hz, 2H), 7.41-7.48 (m, J=8.8 Hz, 2H), 7.18-7.27 (m,4H), 1.27 (s, 9H). MS (M+1): 498

Compound 5-21N-(5-(2-ethoxyphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.73 (d, J=8.8 Hz, 2H), 7.63 (d, J=4.4 Hz,1H), 7.33 (d, J=4.0 Hz, 1H), 7.12-7.05 (m, 2H), 6.98 (dd, J=8.4, 1.6 Hz,1H), 6.88-6.83 (m, 1H), 6.81-6.78 (m, 2H), 4.12 (t, J=6.8 Hz, 2H), 3.85(t, J=6.8 Hz, 2H), 1.75 (sex, J=7.2 Hz, 2H), 1.39 (t, J=6.8 Hz, 3H),1.00 (t, J=7.2 Hz, 3H). MS (M+1): 526.

Compound 5-22N-(4-(4-(tert-butyl)phenyl)-5-(3-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.42 (br. s., 1H), 8.18-8.32 (m, 2H), 7.81(d, J=8.8 Hz, 2H), 7.39-7.48 (m, 3H), 7.06-7.13 (m, 1H), 6.97-7.05 (m,2H), 1.27 (s, 9H)

MS (M+1):498

Compound 5-23N-(4-(4-ethoxyphenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.39 (br. s., 1H), 8.18-8.28 (m, 2H),7.75-7.81 (m, J=8.8 Hz, 2H), 7.60-7.67 (m, 1H), 7.49-7.56 (m, 2H),7.43-7.48 (m, 1H), 6.93-6.99 (m, J=8.8 Hz, 2H), 4.02 (q, J=6.8 Hz, 2H),1.31 (t, J=6.8 Hz, 3H). MS (M+1):536

Compound 5-24N-(5-(3-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.39 (s, 1H), 8.25-8.21 (m, 2H), 7.78 (d,J=8.8 Hz, 2H), 7.46-7.40 (m, 1H), 7.08 (td, J=10.4, 2.4 Hz, 1H),7.03-6.97 (m, 4H), 3.93 (t, J=6.8 Hz, 2H), 1.71 (sex, J=6.8 Hz, 2H),0.96 (t, J=7.2 Hz, 3H). MS (M+1):500.

Compound 5-25N-(4-(4-ethoxyphenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.42 (br. s., 1H), 8.18-8.29 (m, 2H),7.72-7.80 (m, 4H), 7.34 (d, J=8.8 Hz, 2H), 6.92-6.99 (m, 2H), 4.01 (q,J=6.8 Hz, 2H), 1.30 (t, J=6.8 Hz, 3H). MS (M+1): 536

Compound 5-265-nitro-N-(4-(4-propoxyphenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.42 (br. s., 1H), 8.18-8.29 (m, 2H), 7.76(d, J=8.8 Hz, 4H), 7.34 (d, J=8.3 Hz, 2H), 6.93-7.00 (m, 2H), 3.91 (t,J=6.6 Hz, 2H), 1.65-1.75 (m, 2H), 0.95 (t, J=7.6 Hz, 3H). MS (M+1):550

Compound 5-27N-(5-(4-bromophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.37 (br. s., 1H), 8.16-8.29 (m, 2H), 7.76(d, J=9.3 Hz, 2H), 7.52-7.60 (m, 2H), 7.07-7.16 (m, 2H), 6.92-7.01 (m,2H), 3.92 (t, J=6.6 Hz, 2H), 1.65-1.76 (m, 2H), 0.95 (t, J=7.6 Hz, 3H).MS (M+1): 559,561

Compound 5-28N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.34 (br. s., 1H), 8.21 (br. s., 2H), 7.78(d, J=6.8 Hz, 2H), 6.91-7.09 (m, 4H), 3.93 (br. s., 2H), 2.34 (br. s.,6H), 1.71 (d, J=6.4 Hz, 2H), 0.92-1.00 (m, 3H). MS (M+1):588.

Compound 5-29N-(5-(4-(tert-butyl)phenoxy)-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.31 (br. s., 1H), 8.21 (br. s., 2H), 7.82(d, J=7.8 Hz, 2H), 7.36-7.46 (m, J=8.3 Hz, 2H), 7.04-7.13 (m, J=8.3 Hz,2H), 6.97 (d, J=8.3 Hz, 2H), 4.03 (q, J=6.7 Hz, 2H), 1.31 (t, J=6.8 Hz,3H), 1.26 (s, 9H). MS (M+1):524

Compound 5-30N-(5-(4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.27 (br, 1H), 7.62-7.58 (m, 3H), 7.28 (d,J=4.4 Hz, 1H), 7.09-6.98 (m, 4H), 6.78-6.74 (m, 2H), 7.04-6.98 (m, 2H),6.84-6.80 (m, 2H), 3.83 (t, J=6.8 Hz, 2H), 1.75 (sex, J=7.2 Hz, 2H),1.00 (t, J=7.2 Hz, 3H). MS (M+1): 500.

Compound 5-31N-(4-(4-fluorophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.88 (d, J=3.9 Hz, 1H), 7.80-7.87 (m, 2H),7.65-7.71 (m, 1H), 7.61 (d, J=4.4 Hz, 1H), 7.41-7.48 (m, 1H), 7.17-7.23(m, 1H), 7.01-7.08 (m, 3H). MS (M+1): 510.

Compound 5-32N-(4-(4-fluorophenyl)-5-(2-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.02 (br. s., 1H), 7.79-7.87 (m, 3H), 7.54(d, J=4.4 Hz, 1H), 7.35 (dt, J=7.9, 1.4 Hz, 1H), 7.18-7.23 (m, 1H),7.11-7.18 (m, 1H), 7.00-7.10 (m, 3H). MS (M+1):526.

Compound 5-33N-(4-(4-fluorophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.05 (br. s., 1H), 7.84 (d, J=3.9 Hz, 1H),7.77-7.83 (m, 2H), 7.53-7.56 (m, 1H), 7.15-7.22 (m, 2H), 7.07-7.14 (m,2H), 7.00-7.07 (m, 2H). MS (M+1): 526.

Compound 5-34N-(4-(4-methoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J=4.4 Hz, 1H), 7.73 (d, J=8.8 Hz,2H), 7.49 (d, J=4.4 Hz, 1H), 7.28-7.37 (m, 2H), 7.06-7.16 (m, 3H), 6.85(d, J=8.8 Hz, 2H), 3.77 (s, 3H). MS (M+1):454.

Compound 5-35N-(5-(4-fluorophenoxy)-4-(4-(methylcarbamoyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.40 (s, 1H), 8.41 (q, 1H), 8.24 (d, J=4.4Hz, 1H), 8.21 (d, J=4.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.4Hz, 2H), 7.30-7.23 (m, 4H), 2.78 (d, J=4.4 Hz, 3H). MS (M+1):499.

Compound 5-36N-(4-(3,5-diethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.28 (s, 1H), 8.24 (br, 1H), 8.20 (d,J=4.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.20-7.16 (m, 3H), 7.03 (d, J=2.4 Hz,2H), 6.41 (t, J=2.4 Hz, 2H), 3.94 (q, J=6.8 Hz, 4H), 1.27 (t, J=6.8 Hz,6H). MS (M+1): 512.

Compound 5-37N-(5-(2,4-difluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.37 (s, 1H), 8.22-8.20 (m, 2H), 7.81 (d,J=8.8 Hz, 2H), 7.55-7.50 (m, 1H), 7.32-7.26 (m, 1H), 7.10-7.06 (m, 1H),7.03-6.99 (m, 2H), 3.94 (t, J=6.8 Hz, 2H), 1.72 (sex, J=7.2 Hz, 2H),0.97 (t, J=7.2 Hz, 3H). MS (M+1): 512.

Compound 5-38N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.48 (s, 1H), 8.25-8.21 (m, 2H), 8.07 (d,J=2.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.68 (dd, J=8.8, 1.6 Hz, 1H),7.30 (d, J=8.4 Hz, 1H), 7.00-6.96 (m, 2H), 3.93 (t, J=6.8 Hz, 2H), 1.70(sex, J=7.2 Hz, 2H), 0.95 (t, J=7.2 Hz, 3H). MS (M+1): 584.

Compound 5-39N-(5-(4-cyanophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.44 (s, 1H), 8.25-8.21 (m, 2H), 7.90-7.86(m, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.35-7.31 (m, 2H), 6.98-6.95 (m, 2H),3.92 (t, J=6.8 Hz, 2H), 1.71 (sex, J=7.2 Hz, 2H), 0.95 (t, J=7.2 Hz,3H). MS (M+1):507.

Compound 5-40N-(5-(4-cyano-2-methoxyphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.39 (s, 1H), 8.23-8.20 (m, 2H), 7.76 (d,J=8.8 Hz, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.39 (dd, J=8.4, 2.0 Hz, 1H),7.15 (d, J=8.4 Hz, 1H), 6.99-6.96 (m, 2H), 3.95 (s, 3H), 3.93 (t, J=6.8Hz, 2H), 1.71 (sex, J=7.2 Hz, 2H), 0.96 (t, J=7.2 Hz, 3H). MS (M+1):537.

Compound 5-41N-(4-(5-(3,3-dimethylbut-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.77-10.06 (m, 2H), 7.85 (d, J=4.4 Hz, 2H),7.54 (d, J=4.4 Hz, 2H), 7.31-7.37 (m, 4H), 7.24 (s, 1H), 7.23 (s, 1H),7.10-7.17 (m, 6H), 6.96 (d, J=3.9 Hz, 2H), 1.28 (s, 9H). MS (M+1): 510

Compound 5-42N-(4-(5-bromothiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.90 (br. s., 1H), 7.85-7.88 (m, 1H), 7.56(d, J=4.4 Hz, 1H), 7.32-7.38 (m, 2H), 7.10-7.18 (m, 4H), 6.92-6.95 (m,1H). MS (M+1): 509.

Compound 5-43N-(4-(5-(3-(dimethylamino)prop-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (d, J=4.4 Hz, 2H), 7.98 (d, J=4.4 Hz,1H), 7.39-7.45 (m, 2H), 7.26-7.30 (m, 2H), 7.15-7.21 (m, 3H), 3.74 (s,2H), 2.41 (s, 6H). MS (M+1): 511.

Compound 5-44N-(5-(3,4-dichlorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.03 (br, 1H), 7.65 (d, J=4.4 Hz, 1H),7.61-7.57 (m, 2H), 7.37-7.35 (m, 2H), 7.18 (d, J=2.8 Hz, 1H), 6.95 (dd,J=8.8, 2.8 Hz, 1H), 6.80-6.77 (m, 2H), 3.85 (t, J=6.4 Hz, 2H), 1.76(sex, J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). MS (M+1): 550.

Compound 5-45N-(5-(2-chloro-4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.05 (br, 1H), 7.68-7.65 (m, 2H), 7.63 (d,J=4.0 Hz, 1H), 7.32 (d, J=4.4 Hz, 1H), 7.20 (dd, J=7.6, 2.8 Hz, 1H),7.02 (dd, J=8.8, 4.8 Hz, 1H), 6.91-6.86 (m, 1H), 6.81-6.77 (m, 2H), 3.85(t, J=6.8 Hz, 2H), 1.76 (sex, J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). MS(M+1): 534.

Compound 5-46 N-(4-(5-(3-(dim ethylamino)prop-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): □8.14 (d, J=4.4 Hz, 2H), 7.98 (d, J=4.4 Hz,1H), 7.39-7.45 (m, 2H), 7.26-7.30 (m, 2H), 7.15-7.21 (m, 3H), 3.74 (s,2H), 2.41 (s, 6H). MS (M+1): 511

Compound 5-47N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrofuran-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.94 (br, 1H), 7.82-7.80 (m, 4H),7.42-7.38 (m, 2H), 7.17-7.14 (m, 3H), 6.97-6.94 (m, 2H), 4.03 (q, J=6.8Hz, 2H), 1.31 (t, J=7.2 Hz, 3H). LCMS, [M+1]⁺: 452.

Compound 5-485-nitro-N-(5-phenoxy-4-(4-propoxyphenyl)thiazol-2-yl)furan-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 7.82-7.77 (m, 4H), 7.42-7.37 (m, 2H),7.17-7.14 (m, 3H), 6.98-6.94 (m, 2H), 3.92 (t, J=6.8 Hz, 2H), 1.71 (sex,J=7.2 Hz, 2H), 0.96 (t, J=7.2 Hz, 3H). LCMS, [M+1]⁺: 466.

Compound 5-49N-(5-(4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.83 (br, 1H), 7.73-7.69 (m, 2H), 7.31 (d,J=4.0 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.12-7.07 (m, 2H), 7.04-6.98 (m,2H), 6.84-6.80 (m, 2H), 3.88 (t, J=6.4 Hz, 2H), 1.77 (sex, J=7.2 Hz,2H), 1.00 (t, J=7.2 Hz, 3H). LCMS, [M+1]⁺: 484.

Compound 5-50N-(5-(3,5-difluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.51 (br, 1H), 7.74 (d, J=4.4 Hz, 1H),7.64-7.61 (m, 2H), 7.44 (d, J=4.0 Hz, 1H), 6.84-6.80 (m, 2H), 6.65-6.58(m, 2H), 6.58-6.52 (m, 1H), 3.87 (t, J=6.8 Hz, 2H), 1.77 (sex, J=7.2 Hz,2H), 1.00 (t, J=7.2 Hz, 3H). MS (M+1): 518.

Compound 5-51N-(4-(6-ethoxypyridin-3-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 8.68 (d, J=2.4 Hz, 1H), 8.04 (dd, J=8.8, 2.4Hz, 1H), 7.88 (d, J=4.4 Hz, 1H), 7.61 (d, J=4.4 Hz, 1H), 7.35-7.30 (m,2H), 7.14-7.08 (m, 3H), 6.70 (d, J=8.8 Hz, 1H), 4.33 (q, J=6.8 Hz, 2H),1.36 (t, J=6.8 Hz, 3H). MS (M+1): 469.

Compound 5-525-nitro-N-(4-(4-propoxyphenyl)-5-(quinolin-8-yloxy)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 13.27 (br, 1H), 8.99 (dd, J=4.4, 1.6 Hz, 1H),8.46 (dd, J=8.4, 1.6 Hz, 1H), 8.21-8.17 (m, 2H), 7.94-7.90 (m, 2H), 7.80(dd, J=8.4, 0.8 Hz, 1H), 7.66 (dd, J=8.4, 4.4 Hz, 1H), 7.55 (t, J=8.0Hz, 1H), 7.39 (dd, J=8.0, 0.8 Hz, 1H), 6.95-6.91 (m, 2H), 3.90 (t, J=6.4Hz, 2H), 1.68 (sex, J=6.8 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H). MS (M+1):533.

Compound 5-53N-(4-(4-ethoxy-2-fluorophenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.68 (br, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.37(t, J=8.8 Hz, 1H), 7.34-7.29 (m, 3H), 7.13-7.09 (m, 3H), 6.56 (dd,J=8.8, 2.4 Hz, 1H), 6.43 (dd, J=12.0, 2.4 Hz, 1H), 3.91 (q, J=7.2 Hz,2H), 1.36 (t, J=7.2 Hz, 3H). MS (M+1): 486.

Compound 5-54N-(4-(4-ethoxyphenyl)-5-(3-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.06 (br, 1H), 7.63 (d, J=4.4 Hz, 1H),7.62-7.59 (m, 2H), 7.32 (d, J=4.4 Hz, 1H), 7.30-7.25 (m, 1H), 6.89 (dd,J=8.8, 2.0 Hz, 1H), 6.84-6.79 (m, 2H), 6.79-6.75 (m, 2H), 3.95 (q, J=6.8Hz, 2H), 1.37 (t, J=6.8 Hz, 3H). MS (M+1): 486.

Compound 5-55N-(4-(4-ethoxyphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.33 (br, 1H), 7.75 (d, J=4.4 Hz, 1H),7.71-7.67 (m, 2H), 7.44 (d, J=4.4 Hz, 1H), 7.08-7.04 (m, 2H), 7.03-6.98(m, 2H), 6.84-6.81 (m, 2H), 6.84-6.80 (m, 2H), 3.99 (q, J=6.8 Hz, 2H),1.38 (t, J=6.8 Hz, 3H). MS (M+1): 486.

Compound 5-56N-(4-(4-butoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.73 (d, J=4.4 Hz, 1H), 7.64-7.71 (m, 2H),7.43 (d, J=4.4 Hz, 1H), 7.28-7.37 (m, 2H), 7.07-7.16 (m, 3H), 6.78-6.86(m, 2H), 3.91 (t, J=6.6 Hz, 2H), 1.68-1.78 (m, 2H), 1.39-1.51 (m, 3H),0.95 (t, J=7.3 Hz, 3H). MS (M+1):496.

Compound 5-57N-(4-(4-ethoxyphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 13.36 (br, 1H), 8.16-8.28 (m, 2H), 7.79-7.85(m, J=8.8 Hz, 2H), 7.38-7.47 (m, 1H), 7.16-7.25 (m, 3H), 6.97-7.02 (m,J=9.3 Hz, 2H), 4.04 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H). MS(M+1):486.

Compound 5-58N-(5-(2-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 13.35 (br, 1H), 8.15-8.29 (m, 2H), 7.75-7.87(m, J=8.8 Hz, 2H), 7.42 (ddd, J=11.4, 8.2, 2.0 Hz, 1H), 7.15-7.25 (m,3H), 6.96-7.03 (m, 2H), 3.94 (t, J=6.6 Hz, 2H), 1.66-1.77 (m, 2H), 0.97(t, J=7.3 Hz, 3H). MS (M+1):500.

Compound 5-595-nitro-N-(4-(4-(tert-pentyl)phenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.64-7.68 (m, 2H), 7.59 (d, J=4.4 Hz, 1H),7.32-7.38 (m, 2H), 7.27 (d, J=3.9 Hz, 1H), 7.20-7.24 (m, 2H), 7.11-7.17(m, 3H), 1.55 (q, J=7.3 Hz, 2H), 1.19 (s, 6H), 0.56-0.62 (m, 3H). MS(M+1):494.

Compound 5-605-nitro-N-(4-(4-nitrophenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.17 (br. s., 1H), 8.20-8.26 (m, 2H),8.08-8.16 (m, 2H), 7.93 (d, J=4.4 Hz, 1H), 7.61 (d, J=3.9 Hz, 1H),7.34-7.42 (m, 2H), 7.12-7.22 (m, 3H). MS (M+1):469.

Compound 5-615-nitro-N-(5-phenoxy-4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.31 (br. s., 1H), 7.80 (d, J=4.4 Hz, 1H),7.50 (d, J=4.4 Hz, 1H), 7.30-7.40 (m, 2H), 7.06-7.16 (m, 3H), 7.05 (s,2H), 3.80 (s, 3H), 3.68-3.77 (m, 8H), 1.23 (t, J=6.8 Hz, 3H). MS(M+1):514.

Compound 5-62N-(4-(4-fluorophenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.12 (br. s., 1H), 7.81-7.87 (m, 2H),7.76-7.81 (m, 1H), 7.46 (d, J=4.4 Hz, 1H), 7.25-7.32 (m, 2H), 6.96-7.09(m, 4H), 1.61 (q, J=7.3 Hz, 2H), 1.25 (s, 6H), 0.67 (t, J=7.3 Hz, 3H).MS (M+1):512.

Compound 5-63N-(5-(4-fluorophenoxy)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.14 (br. s., 1H), 7.60-7.73 (m, 3H), 7.35(dd, J=4.4, 2.0 Hz, 1H), 7.14-7.29 (m, 2H), 7.06-7.14 (m, 2H), 6.95-7.06(m, 2H), 1.57 (q, J=7.3 Hz, 2H), 1.21 (s, 6H), 0.61 (t, J=7.6 Hz, 3H).MS (M+1):512.

Compound 5-64N-(5-(4-(tert-butyl)phenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.83 (br. s., 1H), 7.82-7.91 (m, 3H), 7.52(d, J=4.4 Hz, 1H), 7.29-7.39 (m, 2H), 6.99-7.09 (m, 4H), 1.29 (s, 9H).MS (M+1):498.

Compound 5-65N-(5-(4-butylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ10.02 (br. s., 1H), 7.77-7.89 (m, 3H), 7.46(d, J=4.4 Hz, 1H), 7.08-7.18 (m, 2H), 6.99-7.06 (m, 4H), 2.50-2.63 (m,2H), 1.50-1.59 (m, 2H), 1.33 (dq, J=15.0, 7.2 Hz, 2H), 0.84-0.95 (m,3H). MS (M+1):498.

Compound 5-66N-(5-(4-butoxyphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.79-7.90 (m, 3H), 7.52 (d, J=3.9 Hz, 1H),6.98-7.09 (m, 4H), 6.80-6.88 (m, 2H), 3.92 (t, J=6.4 Hz, 2H), 1.69-1.79(m, 3H), 1.42-1.53 (m, 3H), 0.96 (t, J=7.3 Hz, 3H). MS (M+1):514.

Compound 5-67N-(4-(4-(hexyloxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.73 (br. s., 1H), 7.61-7.72 (m, 3H),7.28-7.40 (m, 3H), 7.07-7.16 (m, 3H), 6.79 (d, J=8.8 Hz, 2H), 3.88 (t,J=6.6 Hz, 2H), 1.67-1.79 (m, 2H), 1.38-1.49 (m, 2H), 1.25-1.38 (m, 4H),0.84-0.94 (m, 3H). MS (M+1):524.

Compound 5-68N-(5-(4-(tert-butyl)phenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.83 (br. s., 1H), 7.82-7.91 (m, 3H), 7.52(d, J=4.4 Hz, 1H), 7.29-7.39 (m, 2H), 6.99-7.09 (m, 4H), 1.29 (s, 9H).MS (M+1):498.

Compound 5-69N-(5-(4-butylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.02 (br. s., 1H), 7.77-7.89 (m, 3H), 7.46(d, J=4.4 Hz, 1H), 7.08-7.18 (m, 2H), 6.99-7.06 (m, 4H), 2.50-2.63 (m,2H), 1.50-1.59 (m, 2H), 1.33 (dq, J=15.0, 7.2 Hz, 2H), 0.84-0.95 (m,3H). MS (M+1):498.

Compound 5-70N-(5-(4-butoxyphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.79-7.90 (m, 3H), 7.52 (d, J=3.9 Hz, 1H),6.98-7.09 (m, 4H), 6.80-6.88 (m, 2H), 3.92 (t, J=6.4 Hz, 2H), 1.69-1.79(m, 3H), 1.42-1.53 (m, 3H), 0.96 (t, J=7.3 Hz, 3H). MS (M+1):514.

Compound 5-715-nitro-N-(5-(4-(tert-pentyl)phenoxy)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 13.42 (br. s., 1H), 8.23 (d, J=7.34 Hz, 2H),8.14 (d, J=6.85 Hz, 2H), 7.82 (d, J=6.85 Hz, 2H), 7.38 (d, J=7.34 Hz,2H), 7.17 (d, J=7.34 Hz, 2H), 1.52-1.64 (m, 2H), 1.23 (s, 6H), 0.62 (s,3H). MS (M+1):562.

Compound 5-72N-(4-(4-butoxyphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.88 (br. s., 1H), 7.61-7.73 (m, 3H), 7.31(d, J=4.4 Hz, 1H), 7.12-7.21 (m, 1H), 7.00-7.12 (m, 3H), 6.77-6.84 (m,2H), 3.89 (t, J=6.4 Hz, 2H), 1.68-1.76 (m, 2H), 1.40-1.50 (m, 2H), 0.95(t, J=7.3 Hz, 3H). MS (M+1):514.

Compound 5-73N-(4-(4-butoxyphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.57-7.65 (m, 3H), 7.31 (d, J=4.4 Hz, 1H),6.98-7.09 (m, 4H), 6.73-6.81 (m, 2H), 3.88 (t, J=6.6 Hz, 2H), 1.67-1.76(m, 2H), 1.39-1.51 (m, 2H), 0.95 (t, J=7.3 Hz, 3H). MS (M+1):514.

Compound 5-74N-(4-(4-(tert-butyl)phenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.46 (br. s., 1H), 8.18-8.27 (m, 2H), 7.78(dd, J=8.8, 6.8 Hz, 4H), 7.44 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H),1.26 (s, 9H). MS (M+1): 548.

Compound 5-75N-(4-(4-(tert-butyl)phenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 13.48 (br. s., 1H), 8.18-8.29 (m, 2H),7.79-7.87 (m, 3H), 7.62-7.70 (m, 1H), 7.42-7.48 (m, 2H), 7.36 (t, J=7.6Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 1.27 (s, 9H) MS (M+1): 548.

Compound 5-765-nitro-N-(4-(4-(pentyloxy)phenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.69 (br. s., 1H), 7.63-7.73 (m, 3H),7.29-7.39 (m, 3H), 7.06-7.16 (m, 3H), 6.79 (d, J=8.8 Hz, 2H), 3.88 (t,J=6.4 Hz, 2H), 1.74 (quin, J=7.0 Hz, 2H), 1.31-1.45 (m, 4H), 0.85-0.95(m, 3H). MS (M+1):510.

Compound 5-775-nitro-N-(5-phenoxy-4-(4-propylphenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.04 (br. s., 1H), 7.61-7.70 (m, 3H),7.31-7.39 (m, 3H), 7.11-7.16 (m, 3H), 7.08 (d, J=8.3 Hz, 2H), 2.42-2.57(m, 2H), 1.48-1.58 (m, 2H), 0.81-0.96 (m, 3H) MS (M+1):466.

Compound 5-78N-(5-(2-fluorophenoxy)-4-(4-propylphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.48 (br. s., 1H), 7.65 (d, J=8.3 Hz, 2H),7.46-7.62 (m, 1H), 7.02-7.23 (m, 7H), 2.38-2.56 (m, 2H), 1.44-1.58 (m,2H), 0.76-0.98 (m, 3H). MS (M+1):484.

Compound 5-79N-(4-(4-butylphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.58-7.66 (m, J=7.8 Hz, 2H), 7.57 (d, J=4.4Hz, 1H), 7.29-7.38 (m, 2H), 7.26 (d, J=4.4 Hz, 1H), 7.09-7.16 (m, 3H),7.02-7.09 (m, J=8.3 Hz, 2H), 2.41-2.61 (m, 2H), 1.41-1.52 (m, 2H), 1.28(dq, J=15.0, 7.2 Hz, 2H), 0.81-0.95 (m, 3H). MS (M+1):480.

Compound 5-80N-(4-(4-butylphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, J=7.8 Hz, 2H), 7.63 (d, J=4.4 Hz,1H), 7.30 (d, J=3.9 Hz, 1H), 7.16-7.24 (m, 1H), 7.03-7.16 (m, 5H),2.47-2.59 (m, 2H), 1.45-1.54 (m, 2H), 1.24-1.35 (m, 2H), 0.85-0.93 (m,3H). MS (M+1):498.

Compound 5-815-nitro-N-(5-phenoxy-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.00 (br. s., 1H), 7.92-8.03 (m, J=8.3 Hz,2H), 7.82 (d, J=4.4 Hz, 1H), 7.55-7.62 (m, J=8.3 Hz, 2H), 7.51 (d, J=4.4Hz, 1H), 7.29-7.42 (m, 2H), 7.09-7.20 (m, 3H). MS (M+1):492.

Compound 5-82N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-N-methyl-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): 7.86 (d, J=4.0 Hz, 1H), 7.70 (d, J=4.4 Hz, 1H),7.29-7.24 (m, 4H), 7.08 (t, J=8.0 Hz, 1H), 7.01-6.99 (m, 2H), 6.97-6.94(m, 2H), 4.04 (q, J=6.8 Hz, 2H), 3.66 (s, 3H), 1.41 (t, J=6.8 Hz, 3H).MS (M+1): 482.

Compound 5-83N-(5-(2-fluorophenoxy)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.87 (br. s., 1H), 8.01-8.08 (m, J=8.3 Hz,2H), 7.81-7.87 (m, 1H), 7.59-7.66 (m, J=8.3 Hz, 2H), 7.54 (d, J=3.9 Hz,1H), 7.04-7.23 (m, 4H). MS (M+1):510.

Compound 5-845-nitro-N-(5-phenoxy-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.87 (br. s., 1H), 7.87-7.92 (m, 2H), 7.84(d, J=4.4 Hz, 1H), 7.51-7.54 (m, 1H), 7.32-7.38 (m, 2H), 7.10-7.21 (m,5H). MS (M+1):508.

Compound 5-85N-(5-(2-fluorophenoxy)-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.58 (br. s., 1H), 7.88 (d, J=8.8 Hz, 2H),7.74 (d, J=4.4 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.04-7.23 (m, 6H). MS(M+1):526.

Compound 5-86N-(5-(4-bromophenoxy)-4-(4-butoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.94 (br. s., 1H), 7.82 (d, J=4.4 Hz, 1H),7.63-7.73 (m, 2H), 7.47-7.54 (m, 1H), 7.35-7.45 (m, 2H), 6.93-7.02 (m,2H), 6.79-6.89 (m, 2H), 3.93 (t, J=6.6 Hz, 2H), 1.69-1.79 (m, 2H),1.40-1.50 (m, 2H), 0.95 (t, J=7.3 Hz, 3H). MS (M+1):574.

Compound 5-87N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-butoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, J=4.4 Hz, 1H), 7.65-7.70 (m, 2H),7.45 (d, J=4.4 Hz, 1H), 6.80-6.85 (m, 4H), 3.92 (t, J=6.6 Hz, 2H), 2.36(s, 6H), 1.69-1.77 (m, 2H), 1.41-1.49 (m, 2H), 0.95 (t, J=7.6 Hz, 3H).MS (M+1):602.

Compound 5-88N-(4-(4-(tert-butyl)phenyl)-5-(4-propylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.23 (br. s., 1H), 7.54-7.65 (m, J=8.3 Hz,2H), 7.45 (d, J=4.4 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.11-7.19 (m, 3H),7.00-7.11 (m, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.54-1.68 (m, 2H), 0.93 (t,J=7.3 Hz, 3H). MS (M+1):522.

Compound 5-89N-(4-(4-(tert-butyl)phenyl)-5-(4-butylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.66 (br. s., 1H), 7.59-7.69 (m, 2H), 7.55(d, J=4.4 Hz, 1H), 7.23-7.29 (m, 3H), 7.11-7.18 (m, 2H), 6.99-7.08 (m,2H), 2.52-2.64 (m, 2H), 1.50-1.60 (m, 2H), 1.30-1.42 (m, 2H), 1.20-1.26(m, 9H), 0.92 (t, J=7.3 Hz, 3H). MS (M+1):536.

Compound 5-90N-(4-(4-butoxyphenyl)-5-(4-(tert-butyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, J=8.3 Hz, 2H), 7.47 (d, J=3.9 Hz,1H), 7.27-7.42 (m, J=8.3 Hz, 2H), 7.17 (d, J=3.4 Hz, 1H), 6.95-7.12 (m,J=8.3 Hz, 2H), 6.71 (d, J=8.3 Hz, 2H), 3.84 (t, J=6.1 Hz, 2H), 1.60-1.85(m, 2H), 1.37-1.60 (m, 2H), 1.30 (s, 9H), 0.95 (t, J=7.3 Hz, 3H). MS(M+1):552.

Compound 5-91N-(4-(4-butoxyphenyl)-5-(4-cyanophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.82 (d, J=4.4 Hz, 1H), 7.57-7.66 (m, 4H),7.55 (d, J=4.4 Hz, 1H), 7.10-7.18 (m, 2H), 6.77-6.87 (m, 2H), 3.91 (t,J=6.6 Hz, 2H), 1.68-1.77 (m, 2H), 1.40-1.51 (m, 2H), 0.94 (t, J=7.3 Hz,3H). MS (M+1):521.

Compound 5-92N-(4-(4-((5-aminopentyl)oxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.32 (br. s., 1H), 8.21 (d, J=1.00 Hz,1H), 7.81 (d, J=8.80 Hz, 2H), 7.73 (br. s., 2H), 7.37-7.45 (m, 2H),7.13-7.20 (m, 2H), 6.96-7.00 (m, 2H), 3.98 (t, J=6.36 Hz, 2H), 2.79 (br.s, 2H), 2.51-2.54 (m, 2H), 1.67-1.78 (m, 2H), 1.54-1.64 (m, 2H),1.40-1.50 (m, 2H). MS (M+1):525.

Compound 5-93N-(4-(4-butoxyphenyl)-5-(4-propylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.28 (br. s., 1H), 7.48-7.66 (m, J=8.8 Hz,2H), 7.42 (d, J=3.9 Hz, 1H), 7.08-7.21 (m, 3H), 6.97-7.08 (m, J=8.3 Hz,2H), 6.69 (d, J=8.8 Hz, 2H), 3.83 (t, J=6.4 Hz, 2H), 2.55 (t, J=7.6 Hz,2H), 1.66-1.84 (m, 2H), 1.50-1.66 (m, 2H), 1.44 (dq, J=14.7, 7.5 Hz,2H), 0.94 (d, J=7.8 Hz, 3H), 0.82-1.05 (m, 3H). MS (M+1):538.

Compound 5-94N-(4-(4-butylphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.99 (br. s., 1H), 7.58-7.68 (m, 3H), 7.35(d, J=4.4 Hz, 1H), 7.05-7.17 (m, 4H), 6.95-7.05 (m, 2H), 2.45-2.58 (m,2H), 1.47-1.57 (m, 2H), 1.25-1.36 (m, 2H), 0.85-0.95 (m, 3H). MS(M+1):498.

Compound 5-95N-(4-(4-(tert-butyl)phenyl)-5-(4-propoxyphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.80 (br. s., 1H), 7.69-7.75 (m, 2H), 7.68(d, J=4.4 Hz, 1H), 7.36 (d, J=4.4 Hz, 1H), 7.29-7.35 (m, 2H), 7.02-7.10(m, 2H), 6.79-6.90 (m, 2H), 3.88 (t, J=6.6 Hz, 2H), 1.73-1.84 (m, 2H),1.26 (s, 9H), 1.02 (t, J=7.3 Hz, 3H). MS (M+1):538.

Compound 5-96N-(5-(4-(tert-butyl)phenoxy)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.18 (br. s., 1H), 7.66-7.71 (m, 2H), 7.62(d, J=4.4 Hz, 1H), 7.33-7.38 (m, 2H), 7.27-7.32 (m, 3H), 7.04-7.10 (m,2H), 1.30 (s, 9H), 1.24 (s, 9H). MS (M+1):536.

Compound 5-97N-(4-(4-(tert-butyl)phenyl)-5-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.94 (br. s., 1H), 7.62 (d, J=8.3 Hz, 2H),7.50 (d, J=3.9 Hz, 1H), 7.29-7.39 (m, J=8.8 Hz, 2H), 7.22-7.28 (m, 2H),7.20 (d, J=4.4 Hz, 1H), 6.99-7.10 (m, J=8.8 Hz, 2H), 1.71 (s, 3H), 1.35(s, 6H), 1.21 (s, 9H), 0.71 (s, 9H). MS (M+1):592.

Compound 5-98N-(4-(4-butoxyphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.07 (br. s., 1H), 7.64-7.70 (m, 2H), 7.63(d, J=4.4 Hz, 1H), 7.32 (d, J=3.9 Hz, 1H), 7.25-7.29 (m, 2H), 7.01-7.08(m, 2H), 6.74-6.81 (m, 2H), 3.89 (t, J=6.6 Hz, 2H), 1.67-1.79 (m, 2H),1.57-1.64 (m, 2H), 1.39-1.51 (m, 2H), 1.25 (s, 6H), 0.95 (t, J=7.3 Hz,3H), 0.67 (t, J=7.3 Hz, 3H) MS (M+1):566.

Compound 5-99N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.16 (br. s., 1H), 7.64-7.69 (m, 1H),7.59-7.64 (m, 2H), 7.33 (d, J=4.4 Hz, 1H), 7.26-7.31 (m, 2H), 6.86 (s,2H), 2.38 (s, 6H), 1.24 (s, 9H). MS (M+1):586.

Compound 5-100N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.90 (d, J=4.4 Hz, 1H), 7.79-7.87 (m, 2H),7.59 (d, J=4.4 Hz, 1H), 7.02-7.10 (m, 2H), 6.83 (s, 2H), 2.37 (s, 6H).MS (M+1):548.

Compound 5-101N-(4-(4-(tert-butyl)phenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.18 (br. s., 1H), 7.69 (d, J=8.3 Hz, 2H),7.62 (d, J=4.4 Hz, 1H), 7.25-7.37 (m, 5H), 7.02-7.14 (m, 2H), 1.59-1.65(m, 2H), 1.26 (s, 6H), 1.24 (s, 9H), 0.67 (t, J=7.3 Hz, 3H). MS(M+1):550.

Compound 5-102N-(5-(4-(tert-butyl)phenoxy)-4-(4-ethylphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.47 (br. s., 1H), 7.64 (d, J=8.3 Hz, 2H),7.57 (d, J=4.4 Hz, 1H), 7.31-7.38 (m, 2H), 7.26 (d, J=3.9 Hz, 1H),7.03-7.10 (m, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.30 (s, 9H), 1.15 (t, J=7.6Hz, 3H). MS (M+1):508.

Compound 5-103N-(4-(4-ethylphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.64 (br. s., 1H), 7.62 (d, J=8.3 Hz, 2H),7.53 (d, J=3.9 Hz, 1H), 7.25-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.03-7.11(m, 4H), 2.53 (q, J=7.8 Hz, 2H), 1.56-1.64 (m, 2H), 1.26 (s, 6H), 1.14(t, J=7.6 Hz, 3H), 0.67 (t, J=7.3 Hz, 3H). MS (M+1):522.

Compound 5-104N-(4-(4-butylphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.23 (br. s., 1H), 7.65 (d, J=7.8 Hz, 2H),7.56-7.62 (m, 1H), 7.25-7.32 (m, 3H), 7.00-7.14 (m, 4H), 2.51 (t, J=7.8Hz, 2H), 1.57-1.65 (m, 2H), 1.44-1.52 (m, 2H), 1.27-1.34 (m, 2H),1.22-1.27 (m, 6H), 0.89 (t, J=7.3 Hz, 3H), 0.67 (t, J=7.6 Hz, 3H). MS(M+1):550.

Compound 5-105N-(4-(4-(tert-butyl)phenyl)-5-(p-tolyloxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.29 (br. s., 1H), 7.66 (d, J=8.8 Hz, 2H),7.60 (d, J=3.9 Hz, 1H), 7.26-7.36 (m, 3H), 7.09-7.17 (m, J=8.3 Hz, 2H),6.97-7.08 (m, 2H), 2.32 (s, 3H), 1.24 (s, 9H) MS (M+1):494.

Compound 5-106 N-(4-(4-butoxyphenyl)-5-(3,5-dimethylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.00 (br. s., 1H), 7.60-7.70 (m, 3H), 7.32(dd, J=4.4, 1.0 Hz, 1H), 6.74-6.81 (m, 3H), 6.73 (s, 2H), 3.89 (t, J=6.6Hz, 2H), 2.28 (s, 6H), 1.67-1.77 (m, 2H), 1.39-1.51 (m, 2H), 0.95 (t,J=7.3 Hz, 3H). MS (M+1):524.

Compound 5-107N-(4-(4-(tert-butyl)phenyl)-5-(4-(dimethylamino)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.62-7.75 (m, 2H), 7.58 (d, J=4.4 Hz, 1H),7.28-7.33 (m, 2H), 7.27 (d, J=4.4 Hz, 1H), 7.00-7.11 (m, 2H), 6.63-6.76(m, 2H), 2.92 (s, 6H), 1.24 (s, 9H). MS (M+1):523.

Compound 5-108N-(4-(4-(tert-butyl)phenyl)-5-(4-morpholinophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.13 (br. s., 1H), 7.66-7.74 (m, 2H), 7.62(d, J=3.9 Hz, 1H), 7.26-7.35 (m, 3H), 7.05-7.12 (m, 2H), 6.83-6.92 (m,2H), 3.85 (dd, J=5.6, 4.2 Hz, 4H), 3.04-3.15 (m, 4H), 1.25 (s, 9H). MS(M+1):565.

Typical synthesis procedure of Compounds of EXAMPLE 6

Synthesis of 1-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)ethan-1-one

AlCl₃ (9.3 g, 70 mmol) was added to a solution of tert-butylbenzene(9.33 g, 69.5 mmol) in 40 mL chloroform at 0° C. by ice bath afterstirred for 20 min, then 2-(4-fluorophenyl)acetyl chloride (10.0 g, 58mmol) in 20 mL CHCl₃ was added drop wise at 0° C. by ice bath. Removeice bath and stirred at room temperature for 1 h. Then, quench with 250mL cold water and extraction with DCM and remove solvent by rota vaporunder vacuum.

The crude product was purified by flash chromatography (hexane:EA=1:0 to9:1) to afford 1-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)ethan-1-one asred solid (12.9 g, 82% yield).

Synthesis of 2-Bromo-1-(4-ethoxyphenyl)ethanone formation

AlCl₃ (0.3 g, 2.22 mmol) was added to a solution of1-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)ethan-1-one (12.0 g, 44 mmol)in CHCl₃ (55 mL) at 0° C. by ice bath and the resulting mixture wereadded Bromine (7.8 g, 49 mmol) in 55 mL CHCl₃ at 0° C. by ice bath andstirred at room temperature for 4 hours. And added Water (400 ml) andextracted with DCM (200 mL). The organic phase is washed with brine,dried (Na₂SO₄) and concentrated in vacuum. The crude product waspurified by flash chromatography (hexane:EA=1:0 to 9:1) to afford2-bromo-1-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)ethan-1-one (12.4 g,yield 80%).

Synthesis of 4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-amine

To a mixture of thiourea (3.24 g, 42.6 mmol) and2-bromo-1-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)ethan-1-one (12.4 g,35.5 mmol) was added 62 mL ethanol. The reaction mixture was heated upto reflux for 16 hours. The reaction was cooled down to 40° C. andremoved Ethanol and extraction with 200 ml EA and 150 ml saturated. Thecrude product was purified by flash chromatography (hexanes:EA=1:0 to8:2) to afford the yellow powder4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-amine 8.8 g, 75%yield.

Synthesis ofN-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

To a solution of 5-nitrothiophene-2-carboxylic acid (5.1 g, 29.4 mmol),4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-amine (8.0 g, 24.5mmol), EDCl (11.3 g, 58.8 mmol) and HOBt (7.95 g, 58.8 mmol) in DCM (600mL) were stirred at room temperature for overnight. Extraction andremove solvent. The crude product was purified by flash chromatography(hexane:EtOAc=1:0 to 7:3) to afford the red solid powder 13.6 g, Thecrude product was slurry by 500 mL DCM at 40° C. (filtrate by 0.45 uM)and 450 mL EtOH 80° C. for 1 h to removed DCM and 200 ml EtOH bydistilled and solution cooled to RT then suction to afford the solidpowderN-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamideas red solid (8.8 g, 74%).

Example 6: Compounds 6-1 to 6-61 Compound 6-15-nitro-N-(4-(3-nitrophenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.41 (br. s., 1H), 8.81 (t, J=1.7 Hz, 1H),8.40 (d, J=8.3 Hz, 1H), 8.28 (d, J=4.4 Hz, 1H), 8.22-8.24 (m, 1H), 8.20(dd, J=8.1, 1.7 Hz, 1H), 8.09 (s, 1H), 7.76 (t, J=8.1 Hz, 1H). MS (M+1):377.

Compound 6-2N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.75 (br. s., 1H), 7.55 (d, J=4.4 Hz, 1H),7.46-7.42 (m, 2H), 7.23-7.15 (m, 5H), 6.96 (d, J=8.0 Hz, 2H), 2.23 (s,3H). MS (M+1): 500.

Compound 6-35-nitro-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.26 (br, 1H), 8.21 (t, J=2.0 Hz, 1H),8.16-8.14 (m, 1H), 7.69 (d, J=4.4 Hz, 1H), 7.64-7.62 (m, 1H), 7.48 (t,J=8.4 Hz, 1H), 7.40 (d, J=4.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.03 (d,J=8.0 Hz, 1H), 2.28 (s, 3H). MS (M+1): 467.

Compound 6-4N-(5-(3,4-dimethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.58 (br, 1H), 7.59 (d, J=4.0 Hz, 1H), 7.29(d, J=4.4 Hz, 1H), 7.21 (d, J=7.6 Hz, 2H), 6.98 (d, J=7.6 Hz, 2H), 6.93(dd, J=8.4, 2.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H),3.88 (s, 3H), 3.67 (s, 3H), 2.24 (s, 3H). MS (M+1): 482

Compound 6-5N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.84 (br, 1H), 7.78 (s, 1H), 7.75 (s, 2H),7.56 (d, J=4.4 Hz, 1H), 7.24 (d, J=4.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H),6.99 (d, J=8.4 Hz, 2H), 2.25 (s, 3H). MS (M+1): 558.

Compound 6-6N-(5-(4-fluorophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.09 (br, 1H), 7.49 (d, J=4.4 Hz, 1H),7.33-7.28 (m, 2H), 7.18 (d, J=4.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H),7.05-6.99 (m, 2H), 6.93 (d, J=7.6 Hz, 2H), 2.21 (s, 3H). MS (M+1): 440.

Compound 6-7N-(4-(4-bromophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.84 (d, J=3.6 Hz, 1H),7.64-7.61 (m, 3H), 7.53-7.49 (m, 2H), 7.21 (s, 1H). MS (M+1): 410.

Compound 6-8N-(4-(3-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.75 (br, 1H), 7.77 (d, J=4.0 Hz, 1H), 7.48(d, J=4.4 Hz, 1H), 7.29-7.26 (m, 3H), 7.20 (s, 1H), 6.85-6.82 (m, 1H).MS (M+1): 362.

Compound 6-9N-(4-(4-bromophenyl)-5-phenylthiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J=4.4 Hz, 1H), 7.65 (d, J=4.4 Hz,1H), 7.40-7.36 (m, 2H), 7.35-7.29 (m, 5H), 7.24-7.21 (m, 2H). MS (M+1):486.

Compound 6-10N-(5-bromo-4-(4-bromophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.67 (br, 1H), 8.24-8.21 (m, 2H),7.87-7.84 (m, 2H), 7.74-7.70 (m, 2H). MS (M+1): 485.

Compound 6-115-nitro-N-(4-(2-nitrophenyl)thiazol-2-yl)thiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.28 (br, 1H), 8.25 (br, 1H), 8.20 (d,J=4.4 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.81-7.75 (m, 2H), 7.67-7.64 (m,2H). MS (M+1):377.

Compound 6-12N-(5-bromo-4-(2-nitrophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.61 (br, 1H), 8.22-8.20 (m, 2H),8.14-8.11 (m, 1H), 7.89-7.85 (m, 1H), 7.78-7.73 (m, 2H). MS (M+1):455.

Compound 6-13N-(5-bromo-4-(3-nitrophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, acetone-d₆): δ 12.19 (br, 1H), 8.12 (t, J=2.0 Hz, 1H),8.51-8.48 (m, 1H), 8.32-8.29 (m, 1H), 8.28 (d, J=4.4 Hz, 1H), 8.14 (d,J=4.4 Hz, 1H), 7.83 (t, J=8.0 Hz, 1H). MS (M+1): 455.

Compound 6-14N-(5-bromo-4-(3-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, acetone-d₆): δ 12.07 (br, 1H), 8.25 (d, J=4.4 Hz, 1H),8.13 (d, J=4.4 Hz, 1H), 7.53-7.47 (m, 2H), 7.41 (t, J=8.0 Hz, 1H),7.02-6.99 (m, 1H), 3.86 (s, 3H). MS (M+1): 440.

Compound 6-15N-(4-(4-ethoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, J=4.0 Hz, 1H), 7.33-7.29 (m, 3H),7.21-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.69-6.66 (m, 2H), 3.93 (q, J=6.8Hz, 2H), 1.37 (t, J=6.8 Hz, 3H). MS (M+1): 470.

Compound 6-16N-(5-(4-fluorophenyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.08 (br, 1H), 7.55 (d, J=4.4 Hz, 1H),7.32-7.27 (m, 3H), 7.19-7.16 (m, 2H), 7.04-6.98 (m, 2H), 6.67-6.64 (m,2H), 3.80 (t, J=6.4 Hz, 2H), 1.76 (sex, J=7.2 Hz, 2H), 1.01 (t, J=7.2Hz, 3H). MS (M+1): 484.

Compound 6-17N-(5-bromo-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.20 (d, J=3.9 Hz, 1H), 7.84 (s, 1H), 7.73(d, J=8.3 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.92(d, J=8.3 Hz, 1H), 4.05 (dd, J=14.4, 7.1 Hz, 2H), 1.33 (q, J=7.3 Hz,3H). MS (M+1):455

Compound 6-18N-(4-(4-butoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.29 (br. s, 1H), 7.47 (d, J=4.4 Hz, 1H),7.34-7.29 (m, 2H), 7.16-7.13 (m, 3H), 7.04-6.99 (m, 2H), 6.63-6.59 (m,2H), 3.81 (t, J=5.6 Hz, 2H), 1.74-1.67 (m, 2H), 1.45 (sex, J=7.2 Hz,2H), 0.96 (t, J=7.2 Hz, 3H). MS (M+1): 498.

Compound 6-19N-(4-(4-ethoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (br. s., 1H), 8.20 (d, J=3.9 Hz, 1H),7.85 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.50-7.61 (m, 1H), 7.38(d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.3 Hz, 1H), 4.05(dq, J=14.3, 7.0 Hz, 2H), 1.33 (q, J=7.3 Hz, 3H). MS (M+1):520

Compound 6-20N-(5-(4-bromo-3-ethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.87 (br, 1H), 7.57 (d, J=4.4 Hz, 1H), 7.52(d, J=8.8 Hz, 1H), 7.29 (d, J=4.4 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.93(d, J=8.0 Hz, 2H), 6.86 (d, J=3.2 Hz, 1H), 6.81 (dd, J=8.8, 2.8 Hz, 1H),4.10 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 1.34 (t, J=6.8 Hz, 3H). MS (M+1):544.

Compound 6-21N-(4-(4-(tert-butyl)phenyl)-5-phenylthiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.87 (br. s, 1H), 7.59 (d, J=4.4 Hz, 1H),7.38-7.31 (m, 6H), 7.28-7.25 (m, 2H), 7.19-7.17 (m, 2H), 1.22 (s, 9H).MS (M+1):464.

Compound 6-22N-(5-(4-methylpiperazin-1-yl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (br, 1H), 8.18 (d, J=4.4 Hz, 1H),8.15 (d, J=4.4 Hz, 1H), 8.05-8.01 (m, 2H), 7.01-6.97 (m, 2H), 3.96 (t,J=6.8 Hz, 2H), 2.90 (t, J=4.4 Hz, 4H), 2.55 (br, 4H), 2.29 (s, 3H), 1.74(sex, J=7.2 Hz, 2H), 0.99 (t, J=7.2 Hz, 3H). MS (M+1):488.

Compound 6-23 ethyl2-(5-nitrothiophene-2-carboxamido)-4-(4-propoxyphenyl)thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆): δ 13.70 (br, 1H), 8.23-8.20 (m, 2H), 7.72 (d,J=8.8 Hz, 2H), 7.01-6.97 (m, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.99 (t, J=6.8Hz, 2H), 1.76 (sex, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.00 (t,J=7.2 Hz, 3H). MS (M+1): 462.

Compound 6-24N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, J=4.4 Hz, 1H), 7.36-7.31 (m, 2H),7.29 (d, J=4.4 Hz, 1H), 7.26-7.23 (m, 2H), 7.19 (d, J=8.4 Hz, 2H),7.06-7.01 (m, 2H), 1.22 (s, 9H). MS (M+1):482.

Compound 6-25N-(4-(2,4-diethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.21 (s, 1H), 8.26-8.20 (m, 2H), 8.05 (br,1H), 7.63 (br, 1H), 6.63-6.61 (m, 2H), 4.16 (q, J=6.8 Hz, 2H), 4.08 (q,J=6.8 Hz, 2H), 1.45 (t, J=6.8 Hz, 3H), 1.34 (t, J=6.8 Hz, 3H). MS(M+1):420.

Compound 6-26N-(4-(4-(dimethylamino)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.27 (s, 1H), 8.25-8.20 (m, 2H), 7.75 (d,J=8.8 Hz, 2H), 7.42 (br, 1H), 6.79-6.75 (m, 2H), 2.94 (s, 6H). MS (M+1):375.

Compound 6-27N-(3,5-difluorophenyl)-4-(4-ethoxyphenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.66 (br, 1H), 10.62 (s, 1H), 8.25-8.22(m, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.34-7.29 (m, 2H), 6.99-6.94 (m, 3H),4.06 (q, J=6.8 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H). MS (M+1):531.

Compound 6-28 N-(4-(4-ethoxyphenyl)-5-(methyl(phenyl)amino)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.28 (br. s., 1H), 8.21 (d, J=4.4 Hz, 2H),7.74 (d, J=7.8 Hz, 2H), 7.23 (t, J=7.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H),6.76-6.85 (m, 3H), 4.02 (q, J=6.8 Hz, 2H), 3.19 (s, 3H), 1.31 (t, J=6.8Hz, 3H). MS (M+1):481

Compound 6-29N-(5-(morpholine-4-carbonyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.19-8.16 (m, 2H), 7.53 (d, J=8.8 Hz, 2H),7.04 (d, J=8.8 Hz, 2H), 3.96 (t, J=6.4 Hz, 2H), 3.16 (br, 8H), 1.73(sex, J=6.8 Hz, 2H), 0.97 (t, J=7.2 Hz, 3H). MS (M+1): 503.

Compound 6-30N-(5-(4-methylpiperazine-1-carbonyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.16 (d, J=4.4 Hz, 1H), 8.07 (d, J=4.4 Hz,1H), 7.53 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 3.97 (t, J=6.8 Hz,2H), 2.19 (br, 10H), 1.74 (sex, J=6.8 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H).MS (M+1): 516.

Compound 6-31N-(2,4-difluorophenyl)-2-(5-nitrothiophene-2-carboxamido)-4-(4-propoxyphenyl)thiazole-5-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 10.12 (s, 1H), 8.30-8.24 (m, 1H), 7.85 (d,J=4.4 Hz, 1H), 7.71 (s, 1H), 7.53-7.50 (m, 3H), 7.02-6.98 (m, 2H),6.86-6.82 (m, 1H), 6.76-6.71 (m, 1H), 3.96 (t, J=6.8 Hz, 2H), 1.84 (sex,J=6.8 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H). MS (M+1): 545.

Compound 6-32N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.41 (br s, 1H), 7.91 (br s, 1H), 7.83 (d,J=4.0 Hz, 1H), 7.60-7.56 (m, 2H), 7.34 (d, J=7.6 Hz, 2H), 7.29 (d, J=7.2Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 2.31 (s, 3H). LCMS, [M+1]⁺: 484.

Compound 6-33N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.39-7.46 (m, 2H), 7.26-7.35 (m, 4H),7.20-7.26 (m, 6H), 6.84-6.90 (m, 2H), 4.21 (s, 2H), 4.03 (q, J=6.8 Hz,2H), 1.41 (t, J=7.1 Hz, 3H) LCMS, [M+1]⁺: 450.

Compound 6-34N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.55-7.62 (m, 1H), 7.25-7.34 (m, 6H),7.17-7.23 (m, 2H), 6.79 (d, J=8.8 Hz, 2H), 4.16 (s, 2H), 3.97 (q, J=6.8Hz, 2H), 1.39 (t, J=7.1 Hz, 3H). MS (M+1): 466

Compound 6-35N-(4-(4-ethoxyphenyl)-5-(4-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.51 (d, J=3.9 Hz, 1H), 7.20-7.29 (m, 2H),7.11-7.20 (m, 3H), 6.99 (t, J=8.8 Hz, 2H), 6.71-6.78 (m, 2H), 4.13 (s,2H), 3.95 (q, J=6.8 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H). MS (M+1): 484.

Compound 6-36N-(4-(4-ethoxyphenyl)-5-(3-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.77 (br. s., 1H), 7.56 (d, J=4.4 Hz, 1H),7.24-7.32 (m, 4H), 6.99 (d, J=8.3 Hz, 1H), 6.94 (td, J=8.3, 2.4 Hz, 1H),6.85-6.90 (m, 1H), 6.73-6.81 (m, 2H), 4.16 (s, 2H), 3.96 (q, J=7.0 Hz,2H), 1.39 (t, J=6.8 Hz, 3H). MS (M+1): 484.

Compound 6-37N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, J=3.9 Hz, 1H), 7.31 (d, J=2.4 Hz,4H), 7.21-7.26 (m, 2H), 7.18 (dd, J=8.8, 5.4 Hz, 2H), 7.01 (t, J=8.8 Hz,2H), 4.18 (s, 2H), 1.23-1.27 (m, 9H). MS (M+1):496.

Compound 6-38N-(4-(4-(tert-butyl)phenyl)-5-(3,5-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, J=4.4 Hz, 1H), 7.20-7.28 (m, 5H),6.87 (dd, J=8.1, 2.2 Hz, 2H), 6.77 (s, 1H), 1.23 (s, 9H). MS (M+1):500.

Compound 6-39N-(4-(4-(tert-butyl)phenyl)-5-(2,4-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.53 (d, J=4.4 Hz, 1H), 7.28 (d, J=6.4 Hz,1H), 7.14-7.23 (m, 5H), 6.84-6.95 (m, 2H), 1.18-1.23 (m, 9H). MS(M+1):500.

Compound 6-40N-(5-(4-fluorophenyl)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 8.06-8.13 (m, 2H), 7.29-7.37 (m, 5H),7.21-7.27 (m, 2H), 7.13-7.21 (m, 2H), 1.54 (q, J=7.3 Hz, 2H), 1.19 (s,6H), 0.57 (t, J=7.3 Hz, 3H). MS (M+1):496.

Compound 6-41N-(4-(4-(tert-butyl)phenyl)-5-(3-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.61 (d, J=4.4 Hz, 1H), 7.28-7.34 (m, 2H),7.25-7.28 (m, 2H), 7.19-7.23 (m, 2H), 7.16 (dt, J=7.8, 1.2 Hz, 1H),6.99-7.08 (m, 2H), 1.20-1.25 (m, 9H). MS (M+1):482.

Compound 6-42 ethyl4-(4-(tert-butyl)phenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 11.32 (br. s., 1H), 7.67 (d, J=3.9 Hz, 1H),7.52-7.60 (m, 2H), 7.30-7.38 (m, 2H), 7.25 (d, J=4.4 Hz, 1H), 4.30 (q,J=7.3 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.27 (s, 9H). MS (M+1):460.

Compound 6-43N-(4-(4-(tert-butyl)phenyl)-5-(4-methylpiperazine-1-carbonyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 8.19 (d, J=4.4 Hz, 2H), 8.12 (d, J=4.4 Hz,2H), 7.56 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 3.30-3.38 (m, 8H),2.14 (s, 3H), 1.32 (s, 9H). MS (M+1): 514

Compound 6-444-(4-(tert-butyl)phenyl)-N-cyclopropyl-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 13.51 (br. s., 1H), 8.34 (d, J=4.4 Hz, 1H),8.21 (d, J=4.4 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H),2.72-2.84 (m, 1H), 1.32 (s, 9H), 0.55-0.71 (m, 2H), 0.39-0.51 (m, 2H).MS (M+1): 471

Compound 6-45 ethyl4-(4-ethoxyphenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 11.04 (br. s., 1H), 7.70 (d, J=3.9 Hz, 1H),7.48-7.61 (m, J=8.8 Hz, 2H), 7.32 (d, J=4.4 Hz, 1H), 6.75-6.87 (m, J=8.8Hz, 2H), 4.29 (q, J=7.3 Hz, 2H), 4.00 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.1Hz, 3H), 1.31 (t, J=7.1 Hz, 3H). MS (M+1):448.

Compound 6-46N-(4-(4-(tert-butyl)phenyl)-5-(3,4-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.31 (br. s., 1H), 7.48 (d, J=3.9 Hz, 1H),7.07-7.22 (m, 8H), 1.20 (s, 9H). MS (M+1):500.

Compound 6-47N-(5-(2,4-difluorophenyl)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.13 (br. s., 1H), 7.52 (d, J=4.4 Hz, 1H),7.27 (td, J=8.3, 6.4 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 7.19 (d, J=4.4 Hz,1H), 7.10 (d, J=8.3 Hz, 2H), 6.84-6.94 (m, 2H), 1.50 (q, J=7.5 Hz, 2H),1.15 (s, 6H), 0.57 (t, J=7.3 Hz, 3H). MS (M+1):514.

Compound 6-48N-(4-(4-(tert-butyl)phenyl)-5-(2-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.99 (s, 1H), 7.54 (d, J=4.4 Hz, 1H),7.27-7.42 (m, 2H), 7.20-7.27 (m, 3H), 7.08-7.18 (m, 4H), 1.20 (s, 9H).MS (M+1):482.

Compound 6-49N-(4-(4-(tert-butyl)phenyl)-5-(morpholine-4-carbonyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 2H), 7.58 (d, J=8.31 Hz, 2H), 7.52(d, J=8.80 Hz, 2H), 3.54 (br. s., 4H), 3.11 (br. s., 4H), 1.31 (s, 9H).MS (M+1):501.

Compound 6-50N-(4-(4-(tert-butyl)phenyl)-5-cyanothiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): 14.17 (br. s., 1H), 8.22 (s, 2H), 7.94-8.01(m, J=8.8 Hz, 2H), 7.57-7.64 (m, J=8.3 Hz, 2H), 1.33 (s, 9H). MS(M+1):413.

Compound 6-51N-(4-(4-(tert-butyl)phenyl)-5-(3,4,5-trifluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.63 (br. s., 1H), 7.29 (br. s., 1H),7.12-7.24 (m, 4H), 6.84-7.02 (m, 3H). MS (M+1):518.

Compound 6-52N-(4-(4-(tert-butyl)phenyl)-5-(2,4,6-trifluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.62 (d, J=4.4 Hz, 1H), 7.29 (d, J=4.4 Hz,1H), 7.22-7.27 (m, 6H), 7.17-7.22 (m, 2H), 6.75 (dd, J=8.6, 7.1 Hz, 2H),1.22 (s, 9H). MS (M+1):518.

Compound 6-53N-(5-(4-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.92 (br. s., 1H), 7.59 (d, J=4.4 Hz, 1H),7.46-7.56 (m, 2H), 7.25-7.30 (m, 7H), 7.20-7.25 (m, 2H), 1.26 (s, 10H).MS (M+1):542.

Compound 6-54N-(4-(4-(tert-butyl)phenyl)-5-(4-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.46 (d, J=4.4 Hz, 1H), 7.26-7.32 (m, 2H),7.21-7.25 (m, 3H), 7.10-7.16 (m, 3H), 6.84-6.91 (m, 2H), 3.83 (s, 3H),1.16-1.21 (m, 9H). MS (M+1):494.

Compound 6-55N-(4-(4-(tert-butyl)phenyl)-5-(2-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, J=3.9 Hz, 1H), 7.51 (dd, J=8.1, 1.2Hz, 1H), 7.32-7.40 (m, 2H), 7.25-7.32 (m, 2H), 7.18-7.23 (m, 2H),7.12-7.18 (m, 2H), 1.20 (s, 9H). MS (M+1):498.

Compound 6-56N-(4-(4-(tert-butyl)phenyl)-5-(3-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.10 (br. s., 1H), 7.52 (d, J=3.9 Hz, 1H),7.35 (t, J=1.7 Hz, 1H), 7.25-7.32 (m, 2H), 7.20-7.24 (m, 3H), 7.15-7.20(m, 3H), 1.21 (s, 9H). MS (M+1):498.

Compound 6-57N-(5-(2-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 7.57 (d, J=4.4 Hz, 1H), 7.50 (t, J=1.7 Hz,1H), 7.45 (dt, J=7.8, 1.5 Hz, 1H), 7.24-7.31 (m, 3H), 7.16-7.24 (m, 4H),1.22 (s, 10H). MS (M+1):542.

Compound 6-58N-(5-(3-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 12.21 (br. s., 1H), 7.69-7.74 (m, 1H), 7.53(d, J=4.4 Hz, 1H), 7.26-7.37 (m, 3H), 7.21 (d, J=4.4 Hz, 1H), 7.15-7.20(m, 2H), 7.08-7.14 (m, 2H), 1.18 (s, 9H). MS (M+1): 542.

Compound 6-59N-(4-(4-(tert-butyl)phenyl)-5-(4-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.47 (br. s., 1H), 7.62 (br. s., 1H),7.24-7.33 (m, 7H), 7.17-7.23 (m, 2H), 1.23 (s, 10H). MS (M+1):498.

Compound 6-60N-(5-bromo-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 11.44 (br. s., 1H), 7.59-7.70 (m, 3H),7.29-7.41 (m, 2H), 7.24-7.29 (m, 1H), 1.27 (s, 9H). MS (M+1):466.

Compound 6-61N-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-5-nitrothiophene-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆): δ 13.19 (s, 1H), 11.55 (s, 1H), 8.18 (d,J=4.4 Hz, 1H), 8.15 (d, J=4.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.67 (d,J=8.4 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H). MS (M+1): 393.

In EXAMPLES 1-6, the detail synthesized procedures of some compounds arenot repeated again if the synthesized procedures thereof are similar tothose of the forgoing compounds.

Example 7: Evaluation of Compounds of Formula (I) in In Vitro Assays

The potency of selected compounds was defined by the growth inhibitionability to the hepatocellular carcinoma cell line Hep3B. The Hep3B cellswere treated with selected compounds for 48 hr under 37° C., 5% CO₂, and95% relative humidity.

The number of treated cells was determined by GE InCell 2200 system, andtreated cells were stained with Hoechst 33342 which can reveal theremained nucleus in culture plate. The proportion of survival cells thenwere calculated with the ratio of treated/non-treated cells. The growthinhibition/cytotoxic effect of selected compounds were evaluated by thefollowing protocol of NCI-60 screening platform. The human tumor celllines are plating on a 96 well plate in a fixed density 24 hr priorcompound treatment. Compounds with multiple concentrations are thenadded into each well for further 48 hr incubation. Cell viability isassessed by MTS method and the potency of compound is represented byGI₅₀ and LC₅₀ calculated by MTS result.

The compounds prepared in EXAMPLES 1-6 were tested in two in vitroassays, and the results are shown in Tables 1-6 shown below. Herein, the“Ratio in 10 μM (%)” in the following Tables 1-6 refers to the ratio ofthe number of tumor cells treated with 10 μM of selected compounds tothe number of non-treated tumer cells.

TABLE 1

Ratio in Compound R₁ R₄ 10 μM (%) 1-1 3-ethoxyphenyl H NA 1-24-ethoxyphenyl H 61% 1-3 2-hydroxyphenyl H NA 1-4 2-nitrophenyl H NA 1-54-(trifluoromethyl)phenyl H NA 1-6 2-methoxyphenyl H NA 1-74-bromophenyl H NA 1-8 4-nitrophenyl H 76% 1-9 4-(dimethylamino)phenyl H60% 1-10 2-propoxyphenyl H 61% 1-11 2-(trifluoromethoxy)phenyl H 68%1-12 4-iodophenyl H 67% 1-13 4-bromo-3-nitrophenyl H 60% 1-144-isopropoxyphenyl H 71% 1-15 2-isopropoxyphenyl H 56% 1-164-(pentan-3-yloxy)phenyl H 84% 1-17 4-propoxyphenyl H 82% 1-182,4-diethoxyphenyl H 70% 1-19 4-hydroxyphenyl H NA 1-20 2-butoxyphenyl H81% 1-21 4-butoxyphenyl H 81% 1-22 2-(pentan-3-yloxy)phenyl H 66% 1-232-butoxy-4-ethoxyphenyl H 71% 1-24 2,4,6-triethoxyphenyl H 88% 1-253-ethoxypyridin-4-yl H 54% 1-26 4-ethoxy-2-(ethoxymethoxy)phenyl H 59%1-27 4-ethoxy-2-(2-(4-methylpiperazin-1- H NA yl)ethoxy)phenyl 1-282-(3-(dimethylamino)propoxy)-4- H NA ethoxyphenyl 1-292-(2-(dimethylamino)ethoxy)-4- H NA ethoxyphenyl 1-305-ethoxypyridin-2-yl H 37% 1-31 3-(2-(dimethylamino)ethoxy)pyridin-4-ylH NA 1-32 4-ethoxy-2-(2-methoxyethoxy)phenyl H NA 1-33 4-propylphenyl H44% 1-34 4-ethoxypyridin-3-yl H 78% 1-35 4,6-diethoxypyridin-3-yl H 42%1-36 2,4-diethoxyphenyl Me 53% 1-37 4,6-diethoxypyridin-3-yl Me 47%

TABLE 2

Compound R₁ Ratio in 10 μM (%) 2-1 4-ethoxyphenyl NA 2-2 2-ethoxyphenylNA 2-3 2-propoxyphenyl NA 2-4 2-(trifluoromethoxy)phenyl 88%

TABLE 3

Compound R₁ R₂ Ratio in 10 μM (%) 3-1 3-nitrophenyl p-tolyl NA 3-2phenyl 4-bromophenyl NA 3-3 4-bromophenyl p-tolyl 71% 3-4 4-fluorophenylp-tolyl NA 3-5 3,4-dimethoxyphenyl p-tolyl 85% 3-6 4-fluorophenyl4-propoxyphenyl 83% 3-7 3,5- p-tolyl 78% bis(trifluoromethyl) phenyl 3-8Br 3-methoxyphenyl 84% 3-9 4-fluorophenyl 4-ethoxyphenyl NA 3-104-bromophenyl 4-bromophenyl 52% 3-11 4-ethoxyphenyl H 60% 3-12 H 2,4-50% diethoxyphenyl 3-13 phenoxy 4-ethoxyphenyl 58% 3-14 benzyl4-ethoxyphenyl 76%

TABLE 4

Ratio in 10 Compound R₁ -L-R₃ Y Z₁ Z₂ μM (%) 4-1 4-ethoxyphenylbenzo[d]thiazole- S N N NA 2,6-diamine 4-2 4-ethoxyphenyl 2-(2- S C C89% aminobenzo[d] thiazol-6-yl) 4-3 4-ethoxy-2-(2- 2-(2- N C N 40%methoxyethoxy) aminobenzo[d] H phenyl thiazol-6-yl) 4-4 2,4- 2-(2- N C N40% diethoxyphenyl aminobenzo[d] H thiazol-6-yl)

TABLE 5

Ratio in 10 μM Compound R₂ R₁ M R₄ (%) 5-1 4-bromophenyl phenyl S H 66%5-2 4-bromophenyl 4- S H 60% (trifluoromethoxy) phenyl 5-3 3-nitrophenylphenyl S H 82% 5-4 3 -methoxyphenyl phenyl S H 63% 5-5 2-ethoxyphenylphenyl S H 47% 5-6 4-ethoxyphenyl phenyl S H 42% 5-7 4-bromophenyl4-(trifluoromethyl) S H 31% phenyl 5-8 4-propoxyphenyl 4- S H 24%(trifluoromethoxy) phenyl 5-9 4-propoxyphenyl phenyl S H 32% 5-104-isopropoxyphenyl phenyl S H 29% 5-11 4-bromophenyl 3-(trifluoromethyl)S H 21% phenyl 5-12 2,4-diethoxyphenyl phenyl S H 46% 5-134-propoxyphenyl pyridin-3-yl S H 53% 5-14 4-(tert-butyl)phenyl phenyl SH 50% 5-15 4-(2- pyridin-3-yl S H 54% methoxyethoxy)phenyl 5-16 4-(2-phenyl S H 59% methoxyethoxy)phenyl 5-17 4-propoxyphenyl3-(trifluoromethyl) S H 37% phenyl 5-18 4-bromophenyl 4- S H 37%(trifluoromethoxy) phenyl 5-19 4-bromophenyl 2-(trifluoromethyl) S H 62%phenyl 5-20 4-(tert-butyl)phenyl 4-fluorophenyl S H 62% 5-214-propoxyphenyl 2-ethoxyphenyl S H 28% 5-22 4-(tert-butyl)phenyl 3-fluorophenyl S H 30% 5-23 4-ethoxyphenyl 3-(trifluoromethyl) S H 30%phenyl 5-24 4-propoxyphenyl 3 -fluorophenyl S H 28% 5-25 4-ethoxyphenyl4-(trifluoromethyl) S H 32% phenyl 5-26 4-propoxyphenyl4-(trifluoromethyl) S H 24% phenyl 5-27 4-propoxyphenyl 4-bromophenyl SH 31% 5-28 4-propoxyphenyl 4-bromo-3,5- S H 32% dimethylphenyl 5-294-ethoxyphenyl 4-(tert-butyl) phenyl S H 42% 5-30 4-propoxyphenyl4-fluorophenyl S H 40% 5-31 4-fluorophenyl 2-(trifluoromethyl) S H 48%phenyl 5-32 4-fluorophenyl 2- S H 48% (trifluoromethoxy) phenyl 5-334-fluorophenyl 4- S H 40% (trifluoromethoxy) phenyl 5-34 4-methoxyphenylphenyl S H 54% 5-35 4-(methylcarbamoyl) 4-fluorophenyl S H 68% phenyl5-36 3,5-diethoxyphenyl phenyl S H 39% 5-37 4-propoxyphenyl2,4-difluorophenyl S H 38% 5-38 4-propoxyphenyl 2-chloro-4- S H 41%(trifluoromethyl) phenyl 5-39 4-propoxyphenyl 4-cyanophenyl S H 56% 5-404-propoxyphenyl 4-cyano-2-methoxy S H 46% phenyl 5-413,3-dimethylbut-1-yn- phenyl S H 41% 1-yl)thiophen-2-yl 5-425-bromothiophen-2-yl phenyl S H 55% 5-43 4-propoxyphenyl pyridin-4-yl SH NA 5-44 4-propoxyphenyl 3,4-dichlorophenyl S H 41% 5-454-propoxyphenyl 2-chloro-4-fluoro S H 28% phenyl 5-46 5-(3- phenyl S H53% (dimethylamino)prop- 1-yn-1-yl)thiophen-2- yl 5-47 4-ethoxyphenylphenyl O H NA 5-48 4-propoxyphenyl phenyl O H 37% 5-49 4-propoxyphenyl4-fluorophenyl O H 41% 5-50 4-propoxyphenyl 3,5-difluorophenyl S H 42%5-51 6-ethoxypyridin-3-yl phenyl S H 43% 5-52 4-propoxyphenylquinolin-8-yl S H 41% 5-53 4-ethoxy-2- phenyl S H 41% fluorophenyl 5-544-ethoxyphenyl 3-fluorophenyl S H 35% 5-55 4-ethoxyphenyl 4-fluorophenylS H 47% 5-56 4-butoxyphenyl phenyl S H 40% 5-57 4-ethoxyphenyl2-fluorophenyl S H 43% 5-58 4-propoxyphenyl 2-fluorophenyl S H 43% 5-594-(tert-butyl)phenyl phenyl S H 38% 5-60 4-nitrophenyl phenyl S H 38%5-61 3,4,5- phenyl S H 59% trimethoxyphenyl 5-62 4-fluorophenyl 4-(tert-S H 45% pentyl)phenyl 5-63 4-(tert-pentyl)phenyl 4-fluorophenyl S H 37%5-64 4-fluorophenyl 4-(tert- S H 54% pentyl)phenyl 5-65 4-fluorophenyl4-butylphenyl S H 43% 5-66 4-fluorophenyl 4-butoxyphenyl S H 43% 5-674-(hexyloxy)phenyl phenyl S H 46% 5-68 4-fluorophenyl4-(tert-butyl)phenyl S H 54% 5-69 4-fluorophenyl 4-butylphenyl S H 43%5-70 4-fluorophenyl 4-butoxyphenyl S H 43% 5-71 4- 4-(tert- S H 49%(trifluoromethyl)phenyl pentyl)phenyl 5-72 4-butoxyphenyl 2-fluorophenylS H 43% 5-73 4-butoxyphenyl 4-fluorophenyl S H 49% 5-744-(tert-butyl)phenyl 4- S H 33% (trifluoromethyl) phenyl 5-754-(tert-butyl)phenyl 4- S H 34% (trifluoromethyl) phenyl 5-764-(pentyloxy)phenyl phenyl S H 38% 5-77 4-propylphenyl phenyl S H 33%5-78 4-propylphenyl 2-fluorophenyl S H 33% 5-79 4-butylphenyl phenyl S H31% 5-80 4-butylphenyl 2-fluorophenyl S H 26% 5-81 4- phenyl S H 30%(trifluoromethyl)phenyl 5-82 4-ethoxyphenyl phenyl S methyl 59% 5-83 4-2-fluorophenyl S H 36% (trifluoromethyl)phenyl 5-84 4- phenyl S H 34%(trifluoromethoxy) phenyl 5-85 4- 2-fluorophenyl S H 34%(trifluoromethoxy) phenyl 5-86 4-butoxyphenyl 4-bromophenyl S H 24% 5-874-butoxyphenyl 4-bromo-3,5- S H 36% dimethylphenyl 5-88 4-propylphenoxy4-propylphenyl S H 36% 5-89 4-(tert-butyl)phenyl 4-butylphenyl S H 36%5-90 4-butoxyphenyl 4-(tert-butyl)phenyl S H 48% 5-91 4-butoxyphenyl4-cyanophenyl S H 46% 5-92 5-phenoxypentan-1- phenyl S H 46% amine 5-934-butoxyphenyl 4-propylphenyl S H 45% 5-94 4-butylphenyl 4-fluorophenylS H 32% 5-95 4-(tert-butyl)phenyl 4-propoxyphenyl S H 38% 5-964-(tert-butyl)phenyl 4-(tert-butyl) phenyl S H 47% 5-974-(tert-butyl)phenyl 2,4,4- S H NA trimethylpentan-2-yl phenyl 5-984-butoxyphenyl 4-(tert-pentyl) S H 50% phenyl 5-99 4-(tert-butyl)phenyl4-bromo-3,5- S H 40% dimethyl phenyl 5-100 4-fluorophenyl 4-bromo-3,5- SH 30% dimethyl phenyl 5-101 4-(tert-butyl)phenyl 4-(tert-pentyl) S H 48%phenyl 5-102 4-ethylphenyl 4-(tert-butyl)phenyl S H 40% 5-1034-ethylphenyl 4-(tert-pentyl) S H 33% phenyl 5-104 4-butylphenyl4-(tert-pentyl) S H 56% phenyl 5-105 4-(tert-butyl)phenyl 4-tolyl S H30% 5-106 4-butoxyphenyl 3,5-dimethyl phenyl S H 29% 5-1074-(tert-butyl)phenyl 4-(dimethylamino) S H NA phenyl 5-1084-(tert-butyl)phenyl 4-morpholino S H NA phenyl

TABLE 6

Ratio Com in 10 pound R₂ -X-R₁ M Y Z₃ Z₂ μM (%) 6-1 3-nitrophenyl H S SC N NA 6-2 p-tolyl 4-bromophenyl S S C N NA 6-3 p-tolyl 3-nitrophenyl SS C N 84% 6-4 p-tolyl 3,4-dimethoxy S S C N 64% phenyl 6-5 p-tolyl 3,5-S S C N 46% bis(trifluoro methyl)phenyl 6-6 p-tolyl 4-fluorophenyl S S CN 48% 6-7 4-bromophenyl H S S C N 81% 6-8 3-methoxyphenyl H S S C N NA6-9 4-bromophenyl phenyl S S C N 71% 6-10 4-bromophenyl Br S S C N 50%6-11 2-nitrophenyl H S S C N 62% 6-12 2-nitrophenyl Br S S C N 67% 6-133-nitrophenyl Br S S C N 81% 6-14 3-methoxyphenyl Br S S C N 83% 6-154-ethoxyphenyl 4-fluorophenyl S S C N 64% 6-16 4-propoxyphenyl4-fluorophenyl S S C N 59% 6-17 4-ethoxyphenyl Br S S C N 53% 6-184-butoxyphenyl 4-fluorophenyl S S C N 26% 6-19 4-ethoxyphenyl 4- S S C N26% (trifluoromethyl) phenoxy 6-20 p-tolyl 4-bromo-3- S S C N 45%ethoxyphenyl 6-21 4-(tert- phenyl S S C N 29% butyl)phenyl 6-224-propoxyphenyl 4-methyl S S C N 29% piperazin- 1-yl 6-234-propoxyphenyl Ethyl S S C N 33% carboxylate 6-24 4-(tert-4-fluorophenyl S S C N 30% butyl)phenyl 6-25 3,5- H S S C N NAdiethoxyphenyl 6-26 4- H S S C N NA (dimethylamino) phenyl 6-274-ethoxyphenyl N-(3,5- S S C N 36% difluorophenyl) carboxamide 6-284-ethoxyphenyl methyl(phenyl) S S C N 31% amino 6-29 4-propoxyphenylmorpholine-4- S S C N 58% carbonyl 6-30 4-propoxyphenyl 4-methyl S S C N58% piperazine- 1-carbonyl 6-31 4-propoxyphenyl N-(2,4- S S C N 61%difluorophenyl) formamide 6-32 p-tolyl 4-bromophenyl O S C N 27% 6-334-ethoxyphenyl benzyl O S C N 27% 6-34 4-ethoxyphenyl benzyl S S C N 44%6-35 4-ethoxyphenyl 4-fluorobenzyl S S C N 47% 6-36 4-ethoxyphenyl3-fluorobenzyl S S C N 41% 6-37 4-(tert- 4-fluorobenzyl S S C N 39%butyl)phenyl 6-38 4-(tert- 3,5- S S C N 30% butyl)phenyl difluorophenyl6-39 4-(tert- 2,4- S S C N 31% butyl)phenyl difluorophenyl 6-40 4-(tert-4-fluorophenyl S S C N 25% pentyl)phenyl 6-41 4-(tert- 3-fluorophenyl SS C N 36% butyl)phenyl 6-42 4-(tert- ethyl acetate S S C N 49%butyl)phenyl 6-43 4-(tert- 4-methyl S S C N 38% butyl)phenyl piperazine-1-carbonyl 6-44 4-(tert- N- S S C N 81% butyl)phenyl cyclopropylacetamide 6-45 4-ethoxyphenyl ethyl acetate S S C N NA 6-46 4-(tert-3,4- S S C N 31% butyl)phenyl difluorophenyl 6-47 4-(tert- 2,4- S S C N33% pentyl)phenyl difluorophenyl 6-48 4-(tert- 2-fluorophenyl S S C N45% butyl)phenyl 6-49 4-(tert- morpholine-4- S S C N 57% butyl)phenylcarbonyl 6-50 4-(tert- cyano S S C N 53% butyl)phenyl 6-51 4-(tert-3,4,5- S S C N 50% butyl)phenyl trifluorophenyl 6-52 4-(tert- 2,4,6- S SC N 37% butyl)phenyl trifluorophenyl 6-53 4-(tert- 4-bromophenyl S S C N24% butyl)phenyl 6-54 4-(tert- 4- S S C N 25% butyl)phenyl methoxyphenyl6-55 4-(tert- 2-chlorophenyl S S C N 30% butyl)phenyl 6-56 4-(tert-3-chlorophenyl S S C N 28% butyl)phenyl 6-57 4-(tert- 2-bromophenyl S SC N 29% butyl)phenyl 6-58 4-(tert- 3-bromophenyl S S C N 32%butyl)phenyl 6-59 4-(tert- 4-chlorophenyl S S C N 27% butyl)phenyl 6-604-(tert- bromo S S C N 45% butyl)phenyl 6-61 4-bromophenyl — S N N C NAH

Shown in Tables 1-6 are the structures and in vitro activities ofexemplary compounds of formula (I). Most of the disclosed compounds werefound to inhibit the growth of Hep3B cells.

Example 8: Evaluation of Compounds of Formula (I) in In Vitro MTS Assays

The cell viability measurement is based on the NCI-60 screeningmethodology (Nat. Rev. Cancer 6, 813-823, 2006). Briefly, cells areinoculated into 96-well plates at the optimal plating density. After 24h, one of the two plates for each cell line is processed to determine atime zero cell viability (Tz) by MTS assay (Promega). Compounds areadded over a 2-fold serial dilution to provide a total five drugconcentrations plus DMSO control. Plates are incubated for a further 2days, then measured cell viability by MTS assay [control growth (C) andtest growth in the presence of drug at the five concentration levels(Ti)]. Growth inhibition of 50% (GI₅₀) is calculated from[(Ti−Tz)/(C−Tz)]×100=50, which is the drug concentration resulting in a50% reduction of control cells during the drug incubation. The LC₅₀ iscalculated from [(Ti−Tz)/Tz]×100=−50, which is the drug concentrationresulting in a 50% reduction at the end of the drug treatment ascompared to that at the beginning.

The compounds prepared in EXAMPLES 1-6 were tested in two in vitroassays, and the results are shown in Tables 7-8 shown below. Herein,Hep3B refers to hepatocellular carcinoma cell line, SW480 refers tocolon adenocarcinoma cell line, and NCI-H460 refers to human lung cancercell line.

TABLE 7 Hep3B SW480 NCI-H460 Compound GI₅₀ (μM) GI₅₀ (μM) GI₅₀ (μM) 1-20.16 3.55 0.86 1-7 3.17 7.70 NA 1-10 0.17 0.90 NA 1-15 0.17 0.62 NA 1-162.83 7.26 NA 1-17 0.60 1.81 NA 1-18 0.16 0.19 0.20 1-20 0.21 1.15 NA1-22 0.09 1.23 2.67 1-23 0.48 0.52 0.58 1-25 0.17 0.35 0.32 1-26 0.160.21 0.20 1-29 0.20 3.34 5.20 1-32 0.17 0.23 0.14 1-35 0.55 NA 1.42 1-370.84 1.26 1.35 3-3 1.14 7.97 NA 3-4 2.07 NA 3.02 3-9 2.27 8.95 2.39 3-100.51 1.21 0.84 5-6 1.10 2.59 1.17 5-7 0.63 0.32 0.85 5-8 3.43 NA 3.015-9 2.43 NA 1.11 5-10 2.53 NA 0.88 5-11 6.54 7.04 0.63 5-14 0.34 1.511.72 5-17 0.30 1.26 1.16 5-18 3.09 2.52 6.40 5-19 1.79 1.51 2.88 5-200.79 0.88 2.76 5-22 1.43 2.50 2.09 5-23 1.22 6.42 2.49 5-24 0.95 1.141.57 5-26 0.83 1.05 1.15 5-27 0.82 1.23 1.96 5-29 1.84 3.34 3.24 5-300.92 0.53 0.70 5-32 0.46 0.40 0.69 5-38 0.37 0.77 0.57 5-39 0.89 1.490.23 5-48 5.22 1.81 1.40 5-56 0.55 1.54 0.70 5-62 0.45 0.76 0.59 5-630.43 0.88 0.68 5-66 0.52 0.95 0.39 5-67 0.62 1.03 0.79 5-71 0.63 0.811.53 5-74 1.16 0.69 0.72 5-75 0.80 0.73 0.67 5-76 0.56 1.27 0.74 5-800.68 1.46 0.84 5-81 0.98 2.47 0.81 5-85 0.87 1.66 0.75 6-2 1.27 0.97 NA6-5 0.95 1.20 1.12 6-16 1.24 1.89 0.86 6-18 1.38 6.49 2.01 6-21 0.670.49 0.81 6-24 0.99 1.37 1.56 6-34 1.01 2.51 1.40 6-38 0.63 0.74 0.706-40 0.54 0.92 1.88 6-46 0.59 0.68 0.63 6-47 0.59 0.64 0.58 6-53 0.540.62 0.71 6-54 0.61 1.38 0.44 6-59 0.60 0.75 0.70

TABLE 8 Hep3B SW480 NCI-H460 Compound LC₅₀ (μM) LC₅₀ (μM) LC₅₀ (μM) 1-20.48 8.93 1.24 1-7 9.4 NA NA 1-10 0.55 5.17 NA 1-15 0.50 NA NA 1-16 4.34NA NA 1-17 0.89 NA NA 1-18 0.48 0.58 0.60 1-20 0.63 NA NA 1-22 8.36 NANA 1-23 0.48 0.52 0.58 1-25 0.50 1.04 NA 1-26 0.49 0.63 0.59 1-29 1.10NA NA 1-32 0.54 0.69 0.60 1-35 3.68 NA NA 1-37 1.24 NA NA 3-10 1.29 7.086.62 5-6 4.35 5.52 3.99 5-7 1.23 2.80 1.85 5-8 NA NA 4.66 5-9 NA NA 2.865-10 NA NA 5.31 5-11 NA NA 3.98 5-14 7.35 NA NA 5-17 1.60 2.41 2.29 5-184.77 4.75 NA 5-19 3.91 3.94 NA 5-20 2.63 3.73 8.34 5-22 4.03 4.27 4.535-23 3.96 NA 4.43 5-24 2.07 4.23 3.79 5-26 1.18 3.44 3.20 5-27 1.51 4.874.74 5-29 3.86 9.95 9.12 5-30 2.23 2.82 2.15 5-32 2.17 2.26 1.73 5-381.71 3.22 1.43 5-39 5.53 6.54 1.16 5-48 9.41 NA NA 5-56 2.31 9.32 1.555-62 1.16 2.25 1.24 5-63 0.95 1.85 1.11 5-66 0.76 2.81 1.13 5-67 0.691.91 1.35 5-71 0.66 1.72 2.40 5-74 1.68 1.29 1.30 5-75 1.31 1.67 1.115-76 1.72 5.82 1.52 5-80 1.28 4.17 1.75 5-81 4.23 8.60 2.11 5-85 2.545.73 1.58 6-2 1.94 2.72 NA 6-5 1.08 1.41 1.63 6-16 1.83 2.79 1.75 6-182.17 NA 8.26 6-21 1.35 1.47 1.47 6-24 1.93 3.57 4.22 6-34 7.53 NA NA6-38 1.61 4.06 1.65 6-40 3.03 1.35 3.61 6-46 1.10 1.33 0.90 6-47 0.661.39 0.93 6-53 0.62 0.99 1.37 6-54 0.71 2.35 1.59 6-59 0.64 1.62 1.28

Shown in Tables 7-8 are in vitro activities of exemplary compounds offormula (I). The results indicate that the compounds of the presentdisclosure indeed have efficacy for inhibiting the growth of varioustumor celles.

OTHER EMBODIMENTS

All of the features disclosed in this specification may be combined inany combination. Each feature disclosed in this specification may bereplaced by an alternative feature serving the same, equivalent, orsimilar purpose. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a generic series of equivalent orsimilar features.

Further, from the above description, one skilled in the art can easilyascertain the essential characteristics of the present disclosure, andwithout departing from the spirit and scope thereof, can make variouschanges and modifications of the disclosure to adapt it to varioususages and conditions. Thus, other embodiments are also within theclaims.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein Z₁ is N or C—R₂;Z₂ 1 S C or N; Z₃ is N or C—X—R₁, with the proviso that no more than twoof Z₁, Z₂ and Z₃ are N; X is a direct bond, —(CH₂)_(n)—, —O—, —(C═O)NH—or —(C═O)—, in which n is 1, 2 or 3, and R_(a) is hydrogen or alkyl; Yis —CH—, —NR_(b)—, O or S, in which R_(b) is hydrogen or alkyl; L is adirect bond, —(CH₂)_(m)— or —NH—, in which m is 1, 2 or 3; R₁ ishydrogen, halogen, cyano, alkyl, alkyloxy, cycloalkyl, heterocycloalkyl,aryl or heteroaryl, wherein each of alkyloxy, cycloalkyl,heterocycloalkyl, aryl and heteroaryl is optionally substituted with oneto three moieties selected from the group consisting of halogen,hydroxyl, nitro, cyano, —NR_(c)R_(d), lower alkyl carbamoyl,heterocycloalkyl, alkyl optionally substituted with one to three halo oraryl, and alkyloxy optionally substituted with one to three halo,alkyloxy, cycloalkyl, heterocycloalkyl, —NR_(e)R_(f) or aryl, in whicheach of R_(c), R_(d), R_(e) and R_(f) independently is hydrogen oralkyl; R₂ is hydrogen, halogen, alkyl, alkyloxy, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein each of alkyloxy,cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionallysubstituted with one to three moieties selected from the groupconsisting of halogen, hydroxyl, nitro, cyano, —NR_(g)R_(h), lower alkylcarbamoyl, alkynyl, alkyl optionally substituted with one to three halo,and alkyloxy optionally substituted with one to three halo or alkyloxy,in which each of R_(g) and R_(h) independently is hydrogen or alkyl; R₃is

in which M is O or S; and R₄ is H or alkyl.
 2. The compound or salt ofclaim 1, wherein


3. The compound or salt of claim 1, wherein


4. The compound or salt of claim 3, wherein X is a direct bond.
 5. Thecompound or salt of claim 3, wherein L is a —CH₂—, and R₃ is


6. The compound or salt of claim 3, wherein R₁ is aryl or heteroaryl,wherein each of aryl and heteroaryl is optionally substituted with oneto three moieties selected from the group consisting of halogen,hydroxyl, nitro, cyano, —NR_(c)R_(d), lower alkyl carbamoyl,heterocycloalkyl, alkyl optionally substituted with one to three halo oraryl, and alkyloxy optionally substituted with one to three halo,alkyloxy, cycloalkyl, heterocycloalkyl, —NR_(e)R_(f) or aryl, in whicheach of R_(c), R_(d), R_(e) and R_(f) independently is hydrogen, methylor ethyl.
 7. The compound or salt of claim 6, wherein R₁ is phenyl orpyridinyl, wherein each of phenyl or pyridinyl is optionally substitutedwith one to three alkyloxy optionally substituted with one to threehalo, alkyloxy, cycloalkyl, heterocycloalkyl, —NR_(e)R_(f) or aryl, inwhich each of R_(c), R_(d), R_(e) and R_(f) independently is hydrogen,methyl or ethyl.
 8. The compound or salt of claim 3, wherein R₄ is H ormethyl.
 9. The compound or salt of claim 4, wherein L is a —CH₂—; R₃ is

R₄ is H or methyl; and R₁ is phenyl or pyridinyl, wherein each of phenylor pyridinyl is optionally substituted with one or two ethoxy, butoxy,methoxy substituted with ethoxy, or ethoxy substituted withdimethylamino.
 10. The compound or salt of claim 1, wherein


11. The compound or salt of claim 10, wherein X is a direct bond, —CH₂—,—O—, —N(CH₃)—, —(C═O)NH— or —(C═O)—.
 12. The compound or salt of claim10, wherein L is a direct bond, and R₃ is

in which M is O or S.
 13. The compound or salt of claim 10, wherein Lisa—CH₂—, and R₃ is


14. The compound or salt of claim 10, wherein R₁ is hydrogen, halogen,cyano, alkoxy, aryl or heteroaryl, wherein each of aryl and heteroarylis optionally substituted with one to three moieties selected from thegroup consisting of halogen, hydroxyl, nitro, cyano, —NR_(c)R_(d), loweralkyl carbamoyl, heterocycloalkyl, alkyl optionally substituted with oneto three halo or aryl, and alkyloxy optionally substituted with one tothree halo, alkyloxy, cycloalkyl, heterocycloalkyl, —NR_(e)R_(f) oraryl, in which each of R_(c), R_(d), R_(e) and R_(f) independently ishydrogen, methyl or ethyl.
 15. The compound or salt of claim 14, whereinR₁ is phenyl, which is optionally substituted with one to three moietiesselected from the group consisting of halogen and alkyl optionallysubstituted with one to three halo.
 16. The compound or salt of claim10, wherein R₂ is aryl or heteroaryl, wherein each of aryl andheteroaryl is optionally substituted with one to three moieties selectedfrom the group consisting of halogen, nitro, cyano, lower alkylcarbamoyl, alkynyl, alkyl optionally substituted with one to three halo,and alkyloxy optionally substituted with one to three halo or alkyloxy.17. The compound or salt of claim 16, wherein R₂ is phenyl, which isoptionally substituted with one to three moieties selected from thegroup consisting of halogen, alkyl optionally substituted with one tothree halo, and alkyloxy.
 18. The compound or salt of claim 10, whereinR₄ is H or methyl.
 19. The compound or salt of claim 10, wherein X is—O—; L is a direct bond; R₃ is

in which M is S; R₄ is H; R₁ is phenyl optionally substituted withfluoro, tert-pentyl or trifluoromethyl; and R₂ is phenyl substitutedwith ethoxy, butoxy, fluoro, tert-butyl, tert-pentyl or trifluoromethyl.20. The compound or salt of claim 10, wherein X is a direct bond; L is adirect bond; R₃ is

in which M is S; R₄ is H; R₁ is phenyl optionally substituted with oneor two fluoro; and R₂ is phenyl substituted with tert-butyl ortert-pentyl.
 21. The compound or salt of claim 1, which is any oneselected from the group consisting of Compounds 1-1 to 1-37, Compounds2-1 to 2-4, Compounds 3-1 to 3-14, Compounds 4-1 to 4-4, Compounds 5-1to 5-108, and Compounds 6-1 to 6-61.
 22. A pharmaceutical compositioncomprising a compound or salt of claim 1 and a pharmaceuticallyacceptable carrier.
 23. A method for treating a cancer, comprising:administering to a subject in need thereof an effective amount of acompound or salt of claim
 1. 24. The method of claim 23, wherein thecancer is selected from the group consisting of gastric cancer, coloncancer, colorectal cancer, breast cancer, lung cancer, prostate cancer,bladder cancer, pancreatic cancer, liver cancer, uterine cancer,cervical cancer, endometrial cancer, esophageal cancer, leukemia,lymphoma, kidney cancer, osteosarcoma, ovarian cancer, skin cancer,small intestine cancer, thymus cancer, thyroid cancer, nervous systemcancers, bone cancer, brain cancer, and head and neck cancer.